http://colil.dbcls.jp:18052/sparql?query=define%20sql%3Adescribe-mode%20%22CBD%22%20%20DESCRIBE%20%3Chttp%3A%2F%2Fpurl.jp%2Fbio%2F10%2Fcolil%2Fid%2F24522528%3E&output=application%2Fatom%2Bxml2024-03-29T22:03:08.219389ZOData Service and Descriptor DocumentnodeID://b5446187622024-03-29T22:03:08.219389Z2nodeID://b5446167702024-03-29T22:03:08.219389Z4nodeID://b5446179292024-03-29T22:03:08.219389Z2nodeID://b5446172482024-03-29T22:03:08.219389Z3nodeID://b5446173602024-03-29T22:03:08.219389Z3nodeID://b5446185192024-03-29T22:03:08.219389Z2nodeID://b287419212024-03-29T22:03:08.219389ZDNMT3amut arising earlier in leukemogenesis than NPM1c and FLT3-ITD, a conclusion predicted from recent studies on bulk AML blasts showing that NPM1c and FLT3-ITD occur late and are the only genes recurrently mutated in DNMT3amut AML>>15<<,28,32. Moreover, our findings establish that DNMT3amut occurs in an ancestral cell that gives rise to both T-cells and the dominant AML clone present at diagnosis.nodeID://b5446186312024-03-29T22:03:08.219389Z2nodeID://b5446171172024-03-29T22:03:08.219389Z3nodeID://b5446167542024-03-29T22:03:08.219389Z5nodeID://b5446180692024-03-29T22:03:08.219389Z2nodeID://b5446186152024-03-29T22:03:08.219389Z2nodeID://b5446166232024-03-29T22:03:08.219389Z6nodeID://b5446182962024-03-29T22:03:08.219389Z2nodeID://b5446172132024-03-29T22:03:08.219389Z3nodeID://b5446181652024-03-29T22:03:08.219389Z2nodeID://b5446169692024-03-29T22:03:08.219389Z4nodeID://b5446166072024-03-29T22:03:08.219389Z6nodeID://b5446175592024-03-29T22:03:08.219389Z2nodeID://b5446176712024-03-29T22:03:08.219389Z2nodeID://b5446182612024-03-29T22:03:08.219389Z2nodeID://b5446180182024-03-29T22:03:08.219389Z2nodeID://b5446176552024-03-29T22:03:08.219389Z2nodeID://b5446189262024-03-29T22:03:08.219389Z2nodeID://b5446175242024-03-29T22:03:08.219389Z2nodeID://b5446181142024-03-29T22:03:08.219389Z2nodeID://b5446169182024-03-29T22:03:08.219389Z4nodeID://b5446165992024-03-29T22:03:08.219389Z6nodeID://b5446175082024-03-29T22:03:08.219389Z2nodeID://b5446176202024-03-29T22:03:08.219389Z2nodeID://b5446185722024-03-29T22:03:08.219389Z2nodeID://b5446182102024-03-29T22:03:08.219389Z2nodeID://b5446170582024-03-29T22:03:08.219389Z3nodeID://b5446166952024-03-29T22:03:08.219389Z5nodeID://b5446183292024-03-29T22:03:08.219389Z2nodeID://b5446179662024-03-29T22:03:08.219389Z2nodeID://b5446185562024-03-29T22:03:08.219389Z2nodeID://b5446165642024-03-29T22:03:08.219389Z7nodeID://b5446171542024-03-29T22:03:08.219389Z3nodeID://b5446184252024-03-29T22:03:08.219389Z2nodeID://b5446165482024-03-29T22:03:08.219389Z7nodeID://b5446178192024-03-29T22:03:08.219389Z2nodeID://b5446166602024-03-29T22:03:08.219389Z5nodeID://b5446170232024-03-29T22:03:08.219389Z3nodeID://b5446179312024-03-29T22:03:08.219389Z2nodeID://b5446164172024-03-29T22:03:08.219389Z11nodeID://b5446172502024-03-29T22:03:08.219389Z3nodeID://b5446185212024-03-29T22:03:08.219389Z2nodeID://b287419102024-03-29T22:03:08.219389ZEarly and possibly initiating mutations have been identified from analysis of pre-neoplastic lesions in breast16, lung17, skin18, and colon cancer>>19<<, as well as from studies of AML cases that evolved from a prior myelodysplastic syndrome (MDS)20.nodeID://b5446173692024-03-29T22:03:08.219389Z3nodeID://b5446170072024-03-29T22:03:08.219389Z3nodeID://b5446179152024-03-29T22:03:08.219389Z2nodeID://b5446188672024-03-29T22:03:08.219389Z2nodeID://b5446165132024-03-29T22:03:08.219389Z8nodeID://b5446180712024-03-29T22:03:08.219389Z2nodeID://b5446174652024-03-29T22:03:08.219389Z2nodeID://b5446180552024-03-29T22:03:08.219389Z2nodeID://b5446168592024-03-29T22:03:08.219389Z4nodeID://b5446169712024-03-29T22:03:08.219389Z4nodeID://b5446175612024-03-29T22:03:08.219389Z2nodeID://b5446188322024-03-29T22:03:08.219389Z2nodeID://b5446173182024-03-29T22:03:08.219389Z3nodeID://b5446169552024-03-29T22:03:08.219389Z4nodeID://b5446188162024-03-29T22:03:08.219389Z2nodeID://b5446168242024-03-29T22:03:08.219389Z4nodeID://b5446180202024-03-29T22:03:08.219389Z2nodeID://b5446177762024-03-29T22:03:08.219389Z2nodeID://b5446174142024-03-29T22:03:08.219389Z3nodeID://b5446170952024-03-29T22:03:08.219389Z3nodeID://b5446183662024-03-29T22:03:08.219389Z2nodeID://b5446168082024-03-29T22:03:08.219389Z4nodeID://b5446169202024-03-29T22:03:08.219389Z4nodeID://b5446178722024-03-29T22:03:08.219389Z2nodeID://b5446163582024-03-29T22:03:08.219389Z22nodeID://b5446184622024-03-29T22:03:08.219389Z2nodeID://b5446164702024-03-29T22:03:08.219389Z9nodeID://b5446176292024-03-29T22:03:08.219389Z2nodeID://b5446170602024-03-29T22:03:08.219389Z3nodeID://b5446182192024-03-29T22:03:08.219389Z2nodeID://b5446183312024-03-29T22:03:08.219389Z2nodeID://b5446164542024-03-29T22:03:08.219389Z9nodeID://b5446177252024-03-29T22:03:08.219389Z2nodeID://b5446183152024-03-29T22:03:08.219389Z2nodeID://b5446186772024-03-29T22:03:08.219389Z2nodeID://b5446178212024-03-29T22:03:08.219389Z2nodeID://b5446166692024-03-29T22:03:08.219389Z5nodeID://b5446187732024-03-29T22:03:08.219389Z2nodeID://b5446172592024-03-29T22:03:08.219389Z3nodeID://b5446173712024-03-29T22:03:08.219389Z3nodeID://b5446167652024-03-29T22:03:08.219389Z5nodeID://b5446173552024-03-29T22:03:08.219389Z3nodeID://b5446186262024-03-29T22:03:08.219389Z2nodeID://b5446172242024-03-29T22:03:08.219389Z3nodeID://b5446168612024-03-29T22:03:08.219389Z4nodeID://b5446166182024-03-29T22:03:08.219389Z6nodeID://b5446187222024-03-29T22:03:08.219389Z2nodeID://b5446167302024-03-29T22:03:08.219389Z5nodeID://b5446172082024-03-29T22:03:08.219389Z3nodeID://b5446173202024-03-29T22:03:08.219389Z3nodeID://b5446182722024-03-29T22:03:08.219389Z2nodeID://b5446167142024-03-29T22:03:08.219389Z5nodeID://b5446163952024-03-29T22:03:08.219389Z13nodeID://b5446180292024-03-29T22:03:08.219389Z2nodeID://b5446176662024-03-29T22:03:08.219389Z2nodeID://b5446182562024-03-29T22:03:08.219389Z2nodeID://b5446169292024-03-29T22:03:08.219389Z4nodeID://b5446177622024-03-29T22:03:08.219389Z2nodeID://b5446181252024-03-29T22:03:08.219389Z2nodeID://b5446163602024-03-29T22:03:08.219389Z22nodeID://b5446175192024-03-29T22:03:08.219389Z2nodeID://b5446176312024-03-29T22:03:08.219389Z2nodeID://b5446182212024-03-29T22:03:08.219389Z2nodeID://b5446170692024-03-29T22:03:08.219389Z3nodeID://b5446179772024-03-29T22:03:08.219389Z2nodeID://b5446176152024-03-29T22:03:08.219389Z2nodeID://b5446185672024-03-29T22:03:08.219389Z2nodeID://b5446171652024-03-29T22:03:08.219389Z3nodeID://b5446165592024-03-29T22:03:08.219389Z7nodeID://b5446186632024-03-29T22:03:08.219389Z2nodeID://b5446166712024-03-29T22:03:08.219389Z5nodeID://b5446164282024-03-29T22:03:08.219389Z10nodeID://b5446172612024-03-29T22:03:08.219389Z3nodeID://b5446185322024-03-29T22:03:08.219389Z2nodeID://b5446170182024-03-29T22:03:08.219389Z3nodeID://b5446166552024-03-29T22:03:08.219389Z5nodeID://b5446179262024-03-29T22:03:08.219389Z2nodeID://b5446171302024-03-29T22:03:08.219389Z3nodeID://b5446188782024-03-29T22:03:08.219389Z2nodeID://b5446165242024-03-29T22:03:08.219389Z7nodeID://b5446171142024-03-29T22:03:08.219389Z3nodeID://b5446174762024-03-29T22:03:08.219389Z2nodeID://b5446180662024-03-29T22:03:08.219389Z2nodeID://b5446166202024-03-29T22:03:08.219389Z6nodeID://b5446175722024-03-29T22:03:08.219389Z2nodeID://b5446181622024-03-29T22:03:08.219389Z2nodeID://b5446169662024-03-29T22:03:08.219389Z4nodeID://b5446173292024-03-29T22:03:08.219389Z3nodeID://b5446188272024-03-29T22:03:08.219389Z2nodeID://b5446180312024-03-29T22:03:08.219389Z2nodeID://b5446174252024-03-29T22:03:08.219389Z3nodeID://b5446183772024-03-29T22:03:08.219389Z2nodeID://b5446168192024-03-29T22:03:08.219389Z4nodeID://b5446180152024-03-29T22:03:08.219389Z2nodeID://b5446189232024-03-29T22:03:08.219389Z2nodeID://b5446169312024-03-29T22:03:08.219389Z4nodeID://b5446175212024-03-29T22:03:08.219389Z2nodeID://b5446163692024-03-29T22:03:08.219389Z17nodeID://b5446184732024-03-29T22:03:08.219389Z2nodeID://b5446169152024-03-29T22:03:08.219389Z4nodeID://b5446170712024-03-29T22:03:08.219389Z3nodeID://b5446178672024-03-29T22:03:08.219389Z2nodeID://b5446164652024-03-29T22:03:08.219389Z9nodeID://b5446177362024-03-29T22:03:08.219389Z2nodeID://b5446170552024-03-29T22:03:08.219389Z3nodeID://b5446183262024-03-29T22:03:08.219389Z2nodeI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analysis of FLT3-ITD>>50<< in stem/progenitor, mature lymphoid and blast (CD45dim CD33+) cell populations from patient no.nodeID://b5446188912024-03-29T22:03:08.219389Z2nodeID://b5446170152024-03-29T22:03:08.219389Z3nodeID://b5446173772024-03-29T22:03:08.219389Z3nodeID://b5446188752024-03-29T22:03:08.219389Z2nodeID://b5446168832024-03-29T22:03:08.219389Z4nodeID://b5446165212024-03-29T22:03:08.219389Z7nodeID://b5446174732024-03-29T22:03:08.219389Z2nodeID://b5446187442024-03-29T22:03:08.219389Z2nodeID://b5446180632024-03-29T22:03:08.219389Z2nodeID://b5446168672024-03-29T22:03:08.219389Z4nodeID://b5446187282024-03-29T22:03:08.219389Z2nodeID://b5446167362024-03-29T22:03:08.219389Z5nodeID://b5446188402024-03-29T22:03:08.219389Z2nodeID://b5446173262024-03-29T22:03:08.219389Z3nodeID://b5446182782024-03-29T22:03:08.219389Z2nodeID://b5446168322024-03-29T22:03:08.219389Z4nodeID://b5446177842024-03-29T22:03:08.219389Z2nodeID://b5446174222024-03-29T22:03:08.219389Z3nodeID://b5446183742024-03-29T22:03:08.219389Z2nodeID://b5446177682024-03-29T22:03:08.219389Z2nodeID://b5446178802024-03-29T22:03:08.219389Z2nodeID://b5446163662024-03-29T22:03:08.219389Z18nodeID://b5446184702024-03-29T22:03:08.219389Z2nodeID://b5446176372024-03-29T22:03:08.219389Z2nodeID://b5446182272024-03-29T22:03:08.219389Z2nodeID://b5446164622024-03-29T22:03:08.219389Z9nodeID://b5446177332024-03-29T22:03:08.219389Z2nodeID://b5446183232024-03-29T22:03:08.219389Z2nodeID://b5446186852024-03-29T22:03:08.219389Z2nodeID://b5446172832024-03-29T22:03:08.219389Z3nodeID://b5446186692024-03-29T22:03:08.219389Z2nodeID://b5446166772024-03-29T22:03:08.219389Z5nodeID://b287419362024-03-29T22:03:08.219389ZOur work supports prior studies identifying phenotypic primitive cells that bear only a subset of mutations found in AML blasts26,>>27<<,42. The more precise analysis of highly resolved HSC and progenitor populations that we have undertaken provides novel insight into the identity and proportional contribution of the stem/progenitor populations that acquire pre-leukemicnodeID://b5446187812024-03-29T22:03:08.219389Z2nodeID://b5446172672024-03-29T22:03:08.219389Z3nodeID://b5446185382024-03-29T22:03:08.219389Z2nodeID://b5446171362024-03-29T22:03:08.219389Z3nodeID://b5446167732024-03-29T22:03:08.219389Z4nodeID://b5446186342024-03-29T22:03:08.219389Z2nodeID://b5446172322024-03-29T22:03:08.219389Z3nodeID://b5446166262024-03-29T22:03:08.219389Z6nodeID://b5446181842024-03-29T22:03:08.219389Z2nodeID://b5446187302024-03-29T22:03:08.219389Z2nodeID://b5446175782024-03-29T22:03:08.219389Z2nodeID://b5446181682024-03-29T22:03:08.219389Z2nodeID://b5446182802024-03-29T22:03:08.219389Z2nodeID://b5446167222024-03-29T22:03:08.219389Z5nodeID://b5446180372024-03-29T22:03:08.219389Z2nodeID://b5446176742024-03-29T22:03:08.219389Z2nodeID://b5446175432024-03-29T22:03:08.219389Z2nodeID://b5446181332024-03-29T22:03:08.219389Z2nodeID://b5446169372024-03-29T22:03:08.219389Z4nodeID://b5446177702024-03-29T22:03:08.219389Z2nodeID://b5446178892024-03-29T22:03:08.219389Z2nodeID://b5446175272024-03-29T22:03:08.219389Z2nodeID://b5446184792024-03-29T22:03:08.219389Z2nodeID://b287419172024-03-29T22:03:08.219389ZRecent studies have found that only a subset of mutations contained in AML blasts were present in HSC-enriched cell fractions isolated from AML patient samples, and that these cells were capable of non-leukemic differentiation26,>>27<<. Here we establish that these ancestral preL-HSC present at diagnosis are able to regenerate the entire hematopoietic hierarchy while possessing competitive repopulation advantage over non-leukemic HSC leading to clonal expansion. ThesenodeID://b5446185912024-03-29T22:03:08.219389Z2nodeID://b5446170772024-03-29T22:03:08.219389Z3nodeID://b5446179852024-03-29T22:03:08.219389Z2nodeID://b5446185752024-03-29T22:03:08.219389Z2nodeID://b5446165832024-03-29T22:03:08.219389Z6nodeID://b5446171732024-03-29T22:03:08.219389Z3nodeID://b5446184442024-03-29T22:03:08.219389Z2nodeID://b5446165672024-03-29T22:03:08.219389Z7nodeID://b5446178382024-03-29T22:03:08.219389Z2nodeID://b5446184282024-03-29T22:03:08.219389Z2nodeID://b5446164362024-03-29T22:03:08.219389Z10nodeID://b5446185402024-03-29T22:03:08.219389Z2nodeID://b5446170262024-03-29T22:03:08.219389Z3nodeID://b5446179342024-03-29T22:03:08.219389Z2nodeID://b5446188862024-03-29T22:03:08.219389Z2nodeID://b5446165322024-03-29T22:03:08.219389Z7nodeID://b5446178032024-03-29T22:03:08.219389Z2nodeID://b5446171222024-03-29T22:03:08.219389Z3nodeID://b5446174842024-03-29T22:03:08.219389Z2nodeID://b5446180742024-03-29T22:03:08.219389Z2nodeID://b5446168782024-03-29T22:03:08.219389Z4nodeID://b5446174682024-03-29T22:03:08.219389Z2nodeID://b5446175802024-03-29T22:03:08.219389Z2nodeID://b5446187392024-03-29T22:03:08.219389Z2nodeID://b287419432024-03-29T22:03:08.219389ZAs found originally in these diseases47 and now in AML, in approximately 50% of patients the relapse clone is not related to the predominant clone at diagnosis but rather to a minor leukemic subclone >>10<<,15 or to a predicted ancestral clone47, Our direct demonstration that ancestral clones persist at remission suggests that preL-HSCs are resistant to induction chemotherapy and for some patients they might represent a reservoir from whichnodeID://b5446188512024-03-29T22:03:08.219389Z2nodeID://b5446169742024-03-29T22:03:08.219389Z3nodeID://b5446173372024-03-29T22:03:08.219389Z3nodeID://b5446181702024-03-29T22:03:08.219389Z2nodeID://b5446188352024-03-29T22:03:08.219389Z2nodeID://b5446168432024-03-29T22:03:08.219389Z4nodeID://b5446174332024-03-29T22:03:08.219389Z3nodeID://b5446187042024-03-29T22:03:08.219389Z2nodeID://b5446183852024-03-29T22:03:08.219389Z2nodeID://b5446168272024-03-29T22:03:08.219389Z4nodeID://b5446180232024-03-29T22:03:08.219389Z2nodeID://b5446177792024-03-29T22:03:08.219389Z2nodeID://b5446178912024-03-29T22:03:08.219389Z2nodeID://b5446188002024-03-29T22:03:08.219389Z2nodeID://b5446163772024-03-29T22:03:08.219389Z16nodeID://b287419062024-03-29T22:03:08.219389Zobtained from the same patient has established that the latter frequently do not evolve from the dominant clone, but instead can be traced either to a minor subclone present at diagnosis, or to a putative, undetected ancestral clone>>7<<–15. Thus, a clear understanding of the genomic landscape of tumors is required in order to devise targeting strategies that eliminate not only the dominant clone but also the subclonal reservoirs from which recurrence can arise.nodeID://b5446184812024-03-29T22:03:08.219389Z2nodeID://b5446182382024-03-29T22:03:08.219389Z2nodeID://b5446178752024-03-29T22:03:08.219389Z2nodeID://b5446164732024-03-29T22:03:08.219389Z9nodeID://b5446177442024-03-29T22:03:08.219389Z2nodeID://b5446183342024-03-29T22:03:08.219389Z2nodeID://b5446177282024-03-29T22:03:08.219389Z2nodeID://b5446178402024-03-29T22:03:08.219389Z2nodeID://b5446187922024-03-29T22:03:08.219389Z2nodeID://b5446184302024-03-29T22:03:08.219389Z2nodeID://b5446172782024-03-29T22:03:08.219389Z3nodeID://b5446185492024-03-29T22:03:08.219389Z2nodeID://b5446167842024-03-29T22:03:08.219389Z4nodeID://b5446187762024-03-29T22:03:08.219389Z2nodeID://b5446164222024-03-29T22:03:08.219389Z11nodeID://b5446173742024-03-29T22:03:08.219389Z3nodeID://b5446186452024-03-29T22:03:08.219389Z2nodeID://b5446167682024-03-29T22:03:08.219389Z5nodeID://b5446172432024-03-29T22:03:08.219389Z3nodeID://b5446168802024-03-29T22:03:08.219389Z4nodeID://b5446174702024-03-29T22:03:08.219389Z2nodeID://b5446166372024-03-29T22:03:08.219389Z6nodeID://b5446187412024-03-29T22:03:08.219389Z2nodeID://b287419322024-03-29T22:03:08.219389Zhtml, provided by the Walter and Eliza Hall Institute)>>49<<. P-values were derived using two-tailed Student’s t-tests.nodeID://b5446175892024-03-29T22:03:08.219389Z2nodeID://b5446172272024-03-29T22:03:08.219389Z3nodeID://b5446181792024-03-29T22:03:08.219389Z2nodeID://b5446182912024-03-29T22:03:08.219389Z2nodeID://b5446167332024-03-29T22:03:08.219389Z5nodeID://b5446176852024-03-29T22:03:08.219389Z2nodeID://b5446182752024-03-29T22:03:08.219389Z2nodeID://b5446177812024-03-29T22:03:08.219389Z2nodeID://b5446181442024-03-29T22:03:08.219389Z2nodeID://b5446175382024-03-29T22:03:08.219389Z2nodeID://b5446188092024-03-29T22:03:08.219389Z2nodeID://b5446181282024-03-29T22:03:08.219389Z2nodeID://b5446182402024-03-29T22:03:08.219389Z2nodeID://b5446176342024-03-29T22:03:08.219389Z2nodeID://b5446189052024-03-29T22:03:08.219389Z2nodeID://b5446185862024-03-29T22:03:08.219389Z2nodeID://b5446175032024-03-29T22:03:08.219389Z2nodeID://b5446171842024-03-29T22:03:08.219389Z3nodeID://b5446177302024-03-29T22:03:08.219389Z2nodeID://b5446165782024-03-29T22:03:08.219389Z6nodeID://b5446186822024-03-29T22:03:08.219389Z2nodeID://b5446166902024-03-29T22:03:08.219389Z5nodeID://b5446178492024-03-29T22:03:08.219389Z2nodeID://b5446171682024-03-29T22:03:08.219389Z3nodeID://b5446184392024-03-29T22:03:08.219389Z2nodeID://b5446172802024-03-29T22:03:08.219389Z3nodeID://b287419132024-03-29T22:03:08.219389ZIn AML, a subset of cases evolve from a preceding clinically overt phase such as MDS or chronic myeloid leukemia (CML), characterized by clonal expansion of one or more blood lineages>>22<<,23. The founder mutations present in pre-leukemic cells are retained in the AML blasts, implicating them as putative initiating events and establishing clonal expansion as the first step in leukemogenesis. Interestingly, somatic mutationsnodeID://b5446185512024-03-29T22:03:08.219389Z2nodeID://b5446166742024-03-29T22:03:08.219389Z5nodeID://b5446170372024-03-29T22:03:08.219389Z3nodeID://b5446179452024-03-29T22:03:08.219389Z2nodeID://b5446188972024-03-29T22:03:08.219389Z2nodeID://b5446165432024-03-29T22:03:08.219389Z7nodeID://b5446185352024-03-29T22:03:08.219389Z2nodeID://b5446171332024-03-29T22:03:08.219389Z3nodeID://b5446184042024-03-29T22:03:08.219389Z2nodeID://b5446180852024-03-29T22:03:08.219389Z2nodeID://b5446168892024-03-29T22:03:08.219389Z4nodeID://b5446165272024-03-29T22:03:08.219389Z7nodeID://b5446174792024-03-29T22:03:08.219389Z2nodeID://b5446175912024-03-29T22:03:08.219389Z2nodeID://b5446185002024-03-29T22:03:08.219389Z2nodeID://b5446181812024-03-29T22:03:08.219389Z2nodeID://b5446169852024-03-29T22:03:08.219389Z3nodeID://b5446175752024-03-29T22:03:08.219389Z2nodeID://b5446188462024-03-29T22:03:08.219389Z2nodeID://b5446174442024-03-29T22:03:08.219389Z3nodeID://b5446180342024-03-29T22:03:08.219389Z2nodeID://b5446168382024-03-29T22:03:08.219389Z4nodeID://b5446169502024-03-29T22:03:08.219389Z4nodeID://b5446174282024-03-29T22:03:08.219389Z3nodeID://b5446175402024-03-29T22:03:08.219389Z2nodeID://b5446188112024-03-29T22:03:08.219389Z2nodeID://b5446184922024-03-29T22:03:08.219389Z2nodeID://b5446169342024-03-29T22:03:08.219389Z4nodeID://b5446181302024-03-29T22:03:08.219389Z2nodeID://b5446182492024-03-29T22:03:08.219389Z2nodeID://b5446178862024-03-29T22:03:08.219389Z2nodeID://b5446168032024-03-29T22:03:08.219389Z4nodeID://b5446184762024-03-29T22:03:08.219389Z2nodeID://b5446164842024-03-29T22:03:08.219389Z8nodeID://b5446170742024-03-29T22:03:08.219389Z3nodeID://b5446179822024-03-29T22:03:08.219389Z2nodeID://b5446183452024-03-29T22:03:08.219389Z2nodeID://b5446164682024-03-29T22:03:08.219389Z9nodeID://b5446177392024-03-29T22:03:08.219389Z2nodeID://b5446165802024-03-29T22:03:08.219389Z6nodeID://b5446178512024-03-29T22:03:08.219389Z2nodeID://b5446171702024-03-29T22:03:08.219389Z3nodeID://b287419022024-03-29T22:03:08.219389ZThere is overwhelming evidence that virtually all cancers are clonal and represent the progeny of a single cell>>1<<–3. However, the evolutionary trajectory that leads from the first somatic mutation to the eventual development of cancer is not well mapped.nodeID://b5446184412024-03-29T22:03:08.219389Z2nodeID://b5446172892024-03-29T22:03:08.219389Z3nodeID://b5446178352024-03-29T22:03:08.219389Z2nodeID://b5446164332024-03-29T22:03:08.219389Z10nodeID://b5446187872024-03-29T22:03:08.219389Z2nodeID://b5446177042024-03-29T22:03:08.219389Z2nodeID://b5446173852024-03-29T22:03:08.219389Z3nodeID://b5446167792024-03-29T22:03:08.219389Z4nodeID://b5446188832024-03-29T22:03:08.219389Z2nodeID://b5446168912024-03-29T22:03:08.219389Z4nodeID://b5446178002024-03-29T22:03:08.219389Z2nodeID://b5446174812024-03-29T22:03:08.219389Z2nodeID://b5446187522024-03-29T22:03:08.219389Z2nodeID://b5446172382024-03-29T22:03:08.219389Z3nodeID://b5446168752024-03-29T22:03:08.219389Z4nodeID://b5446185092024-03-29T22:03:08.219389Z2nodeID://b5446187362024-03-29T22:03:08.219389Z2nodeID://b5446167442024-03-29T22:03:08.219389Z5nodeID://b5446173342024-03-29T22:03:08.219389Z3nodeID://b5446186052024-03-29T22:03:08.219389Z2nodeID://b5446182862024-03-29T22:03:08.219389Z2nodeID://b5446167282024-03-29T22:03:08.219389Z5nodeID://b5446168402024-03-29T22:03:08.219389Z4nodeID://b5446172032024-03-29T22:03:08.219389Z3nodeID://b5446177922024-03-29T22:03:08.219389Z2nodeID://b5446174302024-03-29T22:03:08.219389Z3nodeID://b5446187012024-03-29T22:03:08.219389Z2nodeID://b5446183822024-03-29T22:03:08.219389Z2nodeID://b5446175492024-03-29T22:03:08.219389Z2nodeID://b5446163902024-03-29T22:03:08.219389Z14nodeID://b5446181392024-03-29T22:03:08.219389Z2nodeID://b5446182512024-03-29T22:03:08.219389Z2nodeID://b5446163742024-03-29T22:03:08.219389Z17nodeID://b5446176452024-03-29T22:03:08.219389Z2nodeID://b5446185972024-03-29T22:03:08.219389Z2nodeID://b5446182352024-03-29T22:03:08.219389Z2nodeID://b5446177412024-03-29T22:03:08.219389Z2nodeID://b5446181042024-03-29T22:03:08.219389Z2nodeID://b5446165892024-03-29T22:03:08.219389Z6nodeID://b5446186932024-03-29T22:03:08.219389Z2nodeID://b5446171792024-03-29T22:03:08.219389Z3nodeID://b5446172912024-03-29T22:03:08.219389Z3nodeID://b5446182002024-03-29T22:03:08.219389Z2nodeID://b5446166852024-03-29T22:03:08.219389Z5nodeID://b5446179562024-03-29T22:03:08.219389Z2nodeID://b5446172752024-03-29T22:03:08.219389Z3nodeID://b5446185462024-03-29T22:03:08.219389Z2nodeID://b5446171442024-03-29T22:03:08.219389Z3nodeID://b5446167812024-03-29T22:03:08.219389Z4nodeID://b5446165382024-03-29T22:03:08.219389Z7nodeID://b5446186422024-03-29T22:03:08.219389Z2nodeID://b5446166502024-03-29T22:03:08.219389Z5nodeID://b5446178092024-03-29T22:03:08.219389Z2nodeID://b5446171282024-03-29T22:03:08.219389Z3nodeID://b5446172402024-03-29T22:03:08.219389Z3nodeID://b5446185112024-03-29T22:03:08.219389Z2nodeID://b5446181922024-03-29T22:03:08.219389Z2nodeID://b5446169962024-03-29T22:03:08.219389Z3nodeID://b5446166342024-03-29T22:03:08.219389Z6nodeID://b5446179052024-03-29T22:03:08.219389Z2nodeID://b5446175862024-03-29T22:03:08.219389Z2nodeID://b5446188572024-03-29T22:03:08.219389Z2nodeID://b5446165032024-03-29T22:03:08.219389Z8nodeID://b5446181762024-03-29T22:03:08.219389Z2nodeID://b5446180452024-03-29T22:03:08.219389Z2nodeID://b5446176822024-03-29T22:03:08.219389Z2nodeID://b5446168492024-03-29T22:03:08.219389Z4nodeID://b5446174392024-03-29T22:03:08.219389Z3nodeID://b5446175512024-03-29T22:03:08.219389Z2nodeID://b5446169452024-03-29T22:03:08.219389Z4nodeID://b5446181412024-03-29T22:03:08.219389Z2nodeID://b5446175352024-03-29T22:03:08.219389Z2nodeID://b5446178972024-03-29T22:03:08.219389Z2nodeID://b5446188062024-03-29T22:03:08.219389Z2nodeID://b5446184872024-03-29T22:03:08.219389Z2nodeID://b5446174042024-03-29T22:03:08.219389Z3nodeID://b5446170852024-03-29T22:03:08.219389Z3nodeID://b5446179932024-03-29T22:03:08.219389Z2nodeID://b5446189022024-03-29T22:03:08.219389Z2nodeID://b5446164792024-03-29T22:03:08.219389Z9nodeID://b5446169102024-03-29T22:03:08.219389Z4nodeID://b5446185832024-03-29T22:03:08.219389Z2nodeID://b5446165912024-03-29T22:03:08.219389Z6nodeID://b5446175002024-03-29T22:03:08.219389Z2nodeID://b5446171812024-03-29T22:03:08.219389Z3nodeID://b5446184522024-03-29T22:03:08.219389Z2nodeID://b5446165752024-03-29T22:03:08.219389Z6nodeID://b5446170502024-03-29T22:03:08.219389Z3nodeID://b5446178462024-03-29T22:03:08.219389Z2nodeID://b5446182092024-03-29T22:03:08.219389Z2nodeID://b5446164442024-03-29T22:03:08.219389Z10nodeID://b5446184362024-03-29T22:03:08.219389Z2nodeID://b5446187982024-03-29T22:03:08.219389Z2nodeID://b5446170342024-03-29T22:03:08.219389Z3nodeID://b5446173962024-03-29T22:03:08.219389Z3nodeID://b5446183052024-03-29T22:03:08.219389Z2nodeID://b5446179422024-03-29T22:03:08.219389Z2nodeID://b5446188942024-03-29T22:03:08.219389Z2nodeID://b5446165402024-03-29T22:03:08.219389Z7nodeID://b5446178112024-03-29T22:03:08.219389Z2nodeID://b5446174922024-03-29T22:03:08.219389Z2nodeID://b5446184012024-03-29T22:03:08.219389Z2nodeID://b5446180822024-03-29T22:03:08.219389Z2nodeID://b5446172492024-03-29T22:03:08.219389Z3nodeID://b5446168862024-03-29T22:03:08.219389Z4nodeID://b5446187472024-03-29T22:03:08.219389Z2nodeID: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studies in T-ALL46 and B-ALL>>7<<,11,14 revealed the existence of genetically diverse subclones at diagnosis.nodeID://b5446176162024-03-29T22:03:08.219389Z2nodeID://b5446172972024-03-29T22:03:08.219389Z3nodeID://b5446182062024-03-29T22:03:08.219389Z2nodeID://b5446178432024-03-29T22:03:08.219389Z2nodeID://b5446164412024-03-29T22:03:08.219389Z10nodeID://b5446187952024-03-29T22:03:08.219389Z2nodeID://b5446177122024-03-29T22:03:08.219389Z2nodeID://b5446173932024-03-29T22:03:08.219389Z3nodeID://b5446186642024-03-29T22:03:08.219389Z2nodeID://b5446183022024-03-29T22:03:08.219389Z2nodeID://b5446167872024-03-29T22:03:08.219389Z4nodeID://b5446186482024-03-29T22:03:08.219389Z2nodeID://b5446166562024-03-29T22:03:08.219389Z5nodeID://b5446187602024-03-29T22:03:08.219389Z2nodeID://b5446172462024-03-29T22:03:08.219389Z3nodeID://b5446185172024-03-29T22:03:08.219389Z2nodeID://b5446181982024-03-29T22:03:08.219389Z2nodeID://b5446167522024-03-29T22:03:08.219389Z5nodeID://b5446173422024-03-29T22:03:08.219389Z3nodeID://b5446165092024-03-29T22:03:08.219389Z8nodeID://b5446186132024-03-29T22:03:08.219389Z2nodeID://b5446182942024-03-29T22:03:08.219389Z2nodeID://b5446172112024-03-29T22:03:08.219389Z3nodeID://b5446176882024-03-29T22:03:08.219389Z2nodeID://b5446166052024-03-29T22:03:08.219389Z6nodeID://b5446183902024-03-29T22:03:08.219389Z2nodeID://b5446175572024-03-29T22:03:08.219389Z2nodeID://b5446181472024-03-29T22:03:08.219389Z2nodeID://b5446167012024-03-29T22:03:08.219389Z5nodeID://b5446163822024-03-29T22:03:08.219389Z16nodeID://b5446180162024-03-29T22:03:08.219389Z2nodeID://b5446176532024-03-29T22:03:08.219389Z2nodeID://b5446189242024-03-29T22:03:08.219389Z2nodeID://b5446182432024-03-29T22:03:08.219389Z2nodeID://b5446179992024-03-29T22:03:08.219389Z2nodeID://b5446189082024-03-29T22:03:08.219389Z2nodeID://b5446169162024-03-29T22:03:08.219389Z4nodeID://b5446181122024-03-29T22:03:08.219389Z2nodeID://b5446185892024-03-29T22:03:08.219389Z2nodeID://b5446165972024-03-29T22:03:08.219389Z6nodeID://b287419282024-03-29T22:03:08.219389ZOnly a single graft contained more than 50% CD33+ myeloid cells, suggesting co-engraftment by a leukemia stem cell (LSC) that was present at low frequency>>38<<. We analyzed by ddPCR 12 of the multilineage xenografts following 16 weeks of repopulation. Ten of these contained a high proportion of cells bearing DNMT3amut without NPM1c (mean allele frequency 57%), whereas both DNMT3amut and NPM1cnodeID://b5446175062024-03-29T22:03:08.219389Z2nodeID://b5446171872024-03-29T22:03:08.219389Z3nodeID://b5446184582024-03-29T22:03:08.219389Z2nodeID://b5446170562024-03-29T22:03:08.219389Z3nodeID://b5446166932024-03-29T22:03:08.219389Z5nodeID://b5446179642024-03-29T22:03:08.219389Z2nodeID://b5446176022024-03-29T22:03:08.219389Z2nodeID://b5446185542024-03-29T22:03:08.219389Z2nodeID://b5446179482024-03-29T22:03:08.219389Z2nodeID://b5446171522024-03-29T22:03:08.219389Z3nodeID://b5446165462024-03-29T22:03:08.219389Z7nodeID://b5446186502024-03-29T22:03:08.219389Z2nodeID://b5446178172024-03-29T22:03:08.219389Z2nodeID://b5446174982024-03-29T22:03:08.219389Z2nodeID://b5446184072024-03-29T22:03:08.219389Z2nodeID://b5446180882024-03-29T22:03:08.219389Z2nodeID://b5446170052024-03-29T22:03:08.219389Z3nodeID://b5446166422024-03-29T22:03:08.219389Z6nodeID://b5446179132024-03-29T22:03:08.219389Z2nodeID://b5446175942024-03-29T22:03:08.219389Z2nodeID://b5446188652024-03-29T22:03:08.219389Z2nodeID://b5446165112024-03-29T22:03:08.219389Z8nodeID://b5446185032024-03-29T22:03:08.219389Z2nodeID://b5446169882024-03-29T22:03:08.219389Z3nodeID://b5446171012024-03-29T22:03:08.219389Z3nodeID://b5446174632024-03-29T22:03:08.219389Z3nodeID://b5446180532024-03-29T22:03:08.219389Z2nodeID://b5446168572024-03-29T22:03:08.219389Z4nodeID://b5446188492024-03-29T22:03:08.219389Z2nodeID://b5446176902024-03-29T22:03:08.219389Z2nodeID://b5446174472024-03-29T22:03:08.219389Z3nodeID://b5446187182024-03-29T22:03:08.219389Z2nodeID://b5446183992024-03-29T22:03:08.219389Z2nodeID://b287419092024-03-29T22:03:08.219389ZEarly and possibly initiating mutations have been identified from analysis of pre-neoplastic lesions in breast16, lung17, skin>>18<<, and colon cancer19, as well as from studies of AML cases that evolved from a prior myelodysplastic syndrome (MDS)20.nodeID://b5446173162024-03-29T22:03:08.219389Z3nodeID://b5446169532024-03-29T22:03:08.219389Z4nodeID://b5446188142024-03-29T22:03:08.219389Z2nodeID://b5446184952024-03-29T22:03:08.219389Z2nodeID://b5446174122024-03-29T22:03:08.219389Z3nodeID://b5446170932024-03-29T22:03:08.219389Z3nodeID://b5446180022024-03-29T22:03:08.219389Z2nodeID://b5446168062024-03-29T22:03:08.219389Z4nodeID://b5446183642024-03-29T22:03:08.219389Z2nodeID://b5446189102024-03-29T22:03:08.219389Z2nodeID://b5446164872024-03-29T22:03:08.219389Z8nodeID://b5446177582024-03-29T22:03:08.219389Z2nodeID://b5446183482024-03-29T22:03:08.219389Z2nodeID://b5446163562024-03-29T22:03:08.219389Z25nodeID://b5446184602024-03-29T22:03:08.219389Z2nodeID://b5446169022024-03-29T22:03:08.219389Z4nodeID://b5446182172024-03-29T22:03:08.219389Z2nodeID://b5446178542024-03-29T22:03:08.219389Z2nodeID://b5446164522024-03-29T22:03:08.219389Z9nodeID://b5446177232024-03-29T22:03:08.219389Z2nodeID://b5446170422024-03-29T22:03:08.219389Z3nodeID://b5446183132024-03-29T22:03:08.219389Z2nodeID://b5446179502024-03-29T22:03:08.219389Z2nodeID://b5446167982024-03-29T22:03:08.219389Z4nodeID://b5446177072024-03-29T22:03:08.219389Z2nodeID://b5446173882024-03-29T22:03:08.219389Z3nodeID://b5446186592024-03-29T22:03:08.219389Z2nodeID://b5446187712024-03-29T22:03:08.219389Z2nodeID://b287419352024-03-29T22:03:08.219389ZPre-leukemic progenitors of varying phenotypes have been reported in other types of hematologic malignancies25,>>39<<–41, although functional studies were limited.nodeID://b5446172572024-03-29T22:03:08.219389Z3nodeID://b5446168942024-03-29T22:03:08.219389Z4nodeID://b5446180902024-03-29T22:03:08.219389Z2nodeID://b5446164012024-03-29T22:03:08.219389Z12nodeID://b5446167632024-03-29T22:03:08.219389Z5nodeID://b5446187552024-03-29T22:03:08.219389Z2nodeID://b5446173532024-03-29T22:03:08.219389Z3nodeID://b5446169902024-03-29T22:03:08.219389Z3nodeID://b5446186242024-03-29T22:03:08.219389Z2nodeID://b5446167472024-03-29T22:03:08.219389Z5nodeID://b5446176992024-03-29T22:03:08.219389Z2nodeID://b5446186082024-03-29T22:03:08.219389Z2nodeID://b5446166162024-03-29T22:03:08.219389Z6nodeID://b5446187202024-03-29T22:03:08.219389Z2nodeID://b5446182892024-03-29T22:03:08.219389Z2nodeID://b5446172062024-03-29T22:03:08.219389Z3nodeID://b5446177952024-03-29T22:03:08.219389Z2nodeID://b5446181582024-03-29T22:03:08.219389Z2nodeID://b5446167122024-03-29T22:03:08.219389Z5nodeID://b5446163932024-03-29T22:03:08.219389Z13nodeID://b5446173022024-03-29T22:03:08.219389Z3nodeID://b5446176642024-03-29T22:03:08.219389Z2nodeID://b5446182542024-03-29T22:03:08.219389Z2nodeID://b5446176482024-03-29T22:03:08.219389Z2nodeID://b5446177602024-03-29T22:03:08.219389Z2nodeID://b5446189192024-03-29T22:03:08.219389Z2nodeID://b5446183502024-03-29T22:03:08.219389Z2nodeID://b5446175172024-03-29T22:03:08.219389Z2nodeID://b5446171982024-03-29T22:03:08.219389Z3nodeID://b5446181072024-03-29T22:03:08.219389Z2nodeID://b5446186962024-03-29T22:03:08.219389Z2nodeID://b5446163422024-03-29T22:03:08.219389Z70nodeID://b5446176132024-03-29T22:03:08.219389Z2nodeID://b5446172942024-03-29T22:03:08.219389Z3nodeID://b5446185652024-03-29T22:03:08.219389Z2nodeID://b5446182032024-03-29T22:03:08.219389Z2nodeID://b5446166882024-03-29T22:03:08.219389Z5nodeID://b5446179592024-03-29T22:03:08.219389Z2nodeID://b5446171632024-03-29T22:03:08.219389Z3nodeID://b5446165572024-03-29T22:03:08.219389Z7nodeID://b5446173902024-03-29T22:03:08.219389Z3nodeID://b287419242024-03-29T22:03:08.219389ZA high resolution 12-parameter sorting strategy>>33<<–35 was employed to isolate non-leukemic hematopoietic stem and progenitor populations, including hematopoietic stem cells/multipotent progenitors (HSC/MPP), multilymphoid progenitors (MLP), common myeloid progenitors (CMP), granulocytenodeID://b5446186612024-03-29T22:03:08.219389Z2nodeID://b5446171472024-03-29T22:03:08.219389Z3nodeID://b5446184182024-03-29T22:03:08.219389Z2nodeID://b5446180992024-03-29T22:03:08.219389Z2nodeID://b5446170162024-03-29T22:03:08.219389Z3nodeID://b5446166532024-03-29T22:03:08.219389Z5nodeID://b5446179242024-03-29T22:03:08.219389Z2nodeID://b5446185142024-03-29T22:03:08.219389Z2nodeID://b5446181952024-03-29T22:03:08.219389Z2nodeID://b5446169992024-03-29T22:03:08.219389Z3nodeID://b5446179082024-03-29T22:03:08.219389Z2nodeID://b5446171122024-03-29T22:03:08.219389Z3nodeID://b5446165062024-03-29T22:03:08.219389Z8nodeID://b5446180642024-03-29T22:03:08.219389Z2nodeID://b5446186102024-03-29T22:03:08.219389Z2nodeID://b5446174582024-03-29T22:03:08.219389Z3nodeID://b5446187292024-03-29T22:03:08.219389Z2nodeID://b5446180482024-03-29T22:03:08.219389Z2nodeID://b5446181602024-03-29T22:03:08.219389Z2nodeID://b5446169642024-03-29T22:03:08.219389Z4nodeID://b5446166022024-03-29T22:03:08.219389Z6nodeID://b5446175542024-03-29T22:03:08.219389Z2nodeID://b5446188252024-03-29T22:03:08.219389Z2nodeID://b5446169482024-03-29T22:03:08.219389Z4nodeID://b5446174232024-03-29T22:03:08.219389Z3nodeID://b5446180132024-03-29T22:03:08.219389Z2nodeID://b5446168172024-03-29T22:03:08.219389Z4nodeID://b5446176502024-03-29T22:03:08.219389Z2nodeID://b5446189212024-03-29T22:03:08.219389Z2nodeID://b5446164982024-03-29T22:03:08.219389Z8nodeID://b5446174072024-03-29T22:03:08.219389Z3nodeID://b5446177692024-03-29T22:03:08.219389Z2nodeID://b5446170882024-03-29T22:03:08.219389Z3nodeID://b5446183592024-03-29T22:03:08.219389Z2nodeID://b5446179962024-03-29T22:03:08.219389Z2nodeID://b5446184712024-03-29T22:03:08.219389Z2nodeID://b5446169132024-03-29T22:03:08.219389Z4nodeID://b287419052024-03-29T22:03:08.219389ZHowever the modern era of cancer genomics has exposed a more complex clonal architecture in many tumor types4, where multiple genetically distinct subclones co-exist with the dominant clone5,>>6<<. Comparison of diagnostic and recurrent/metastatic samples obtained from the same patient has established that the latter frequently do not evolve from the dominant clone, but instead can be traced either to a minor subclone present atnodeID://b5446165942024-03-29T22:03:08.219389Z6nodeID://b5446178652024-03-29T22:03:08.219389Z2nodeID://b5446184552024-03-29T22:03:08.219389Z2nodeID://b5446164632024-03-29T22:03:08.219389Z9nodeID://b5446170532024-03-29T22:03:08.219389Z3nodeID://b5446183242024-03-29T22:03:08.219389Z2nodeID://b5446179612024-03-29T22:03:08.219389Z2nodeID://b5446164472024-03-29T22:03:08.219389Z10nodeID://b5446177182024-03-29T22:03:08.219389Z2nodeID://b5446173992024-03-29T22:03:08.219389Z3nodeID://b5446183082024-03-29T22:03:08.219389Z2nodeID://b5446184202024-03-29T22:03:08.219389Z2nodeID://b5446178142024-03-29T22:03:08.219389Z2nodeID://b5446174952024-03-29T22:03:08.219389Z2nodeID://b5446164122024-03-29T22:03:08.219389Z11nodeID://b5446187662024-03-29T22:03:08.219389Z2nodeID://b5446170022024-03-29T22:03:08.219389Z3nodeID://b5446173642024-03-29T22:03:08.219389Z3nodeID://b5446179102024-03-29T22:03:08.219389Z2nodeID://b5446167582024-03-29T22:03:08.219389Z5nodeID://b5446188622024-03-29T22:03:08.219389Z2nodeID://b5446168702024-03-29T22:03:08.219389Z4nodeID://b5446173482024-03-29T22:03:08.219389Z3nodeID://b5446186192024-03-29T22:03:08.219389Z2nodeID://b5446174602024-03-29T22:03:08.219389Z3nodeID://b287419312024-03-29T22:03:08.219389ZFor limiting dilution assays, the frequency of repopulating cells was calculated using ELDA software>>49<<.nodeID://b5446187312024-03-29T22:03:08.219389Z2nodeID://b5446180502024-03-29T22:03:08.219389Z2nodeID://b5446172172024-03-29T22:03:08.219389Z3nodeID://b5446168542024-03-29T22:03:08.219389Z4nodeID://b5446181692024-03-29T22:03:08.219389Z2nodeID://b5446187152024-03-29T22:03:08.219389Z2nodeID://b5446167232024-03-29T22:03:08.219389Z5nodeID://b5446183962024-03-29T22:03:08.219389Z2nodeID://b5446173132024-03-29T22:03:08.219389Z3nodeID://b5446182652024-03-29T22:03:08.219389Z2nodeID://b5446167072024-03-29T22:03:08.219389Z5nodeID://b5446163882024-03-29T22:03:08.219389Z14nodeID://b5446176592024-03-29T22:03:08.219389Z2nodeID://b5446177712024-03-29T22:03:08.219389Z2nodeID://b5446170902024-03-29T22:03:08.219389Z3nodeID://b5446183612024-03-29T22:03:08.219389Z2nodeID://b5446177552024-03-29T22:03:08.219389Z2nodeID://b5446181182024-03-29T22:03:08.219389Z2nodeID://b5446163532024-03-29T22:03:08.219389Z28nodeID://b5446176242024-03-29T22:03:08.219389Z2nodeID://b5446182142024-03-29T22:03:08.219389Z2nodeID://b5446166992024-03-29T22:03:08.219389Z5nodeID://b5446176082024-03-29T22:03:08.219389Z2nodeID://b5446177202024-03-29T22:03:08.219389Z2nodeID://b5446186722024-03-29T22:03:08.219389Z2nodeID://b5446183102024-03-29T22:03:08.219389Z2nodeID://b5446167952024-03-29T22:03:08.219389Z4nodeID://b5446171582024-03-29T22:03:08.219389Z3nodeID://b5446184292024-03-29T22:03:08.219389Z2nodeID://b5446186562024-03-29T22:03:08.219389Z2nodeID://b5446166642024-03-29T22:03:08.219389Z5nodeID://b5446172542024-03-29T22:03:08.219389Z3nodeID://b5446185252024-03-29T22:03:08.219389Z2nodeID://b5446166482024-03-29T22:03:08.219389Z5nodeID://b5446179192024-03-29T22:03:08.219389Z2nodeID://b5446171232024-03-29T22:03:08.219389Z3nodeID://b5446167602024-03-29T22:03:08.219389Z5nodeID://b5446173502024-03-29T22:03:08.219389Z3nodeID://b5446165172024-03-29T22:03:08.219389Z7nodeID://b287419202024-03-29T22:03:08.219389ZConsistent with published data>>29<<–31, 17 of 71 AML samples (24%) carried mutations in DNMT3a, and 15 of these 17 (88%) also carried NPM1c.nodeID://b5446186212024-03-29T22:03:08.219389Z2nodeID://b5446174692024-03-29T22:03:08.219389Z2nodeID://b5446171072024-03-29T22:03:08.219389Z3nodeID://b5446180592024-03-29T22:03:08.219389Z2nodeID://b5446176962024-03-29T22:03:08.219389Z2nodeID://b5446166132024-03-29T22:03:08.219389Z6nodeID://b5446181712024-03-29T22:03:08.219389Z2nodeID://b5446175652024-03-29T22:03:08.219389Z2nodeID://b5446181552024-03-29T22:03:08.219389Z2nodeID://b5446169592024-03-29T22:03:08.219389Z4nodeID://b5446176612024-03-29T22:03:08.219389Z2nodeID://b5446180242024-03-29T22:03:08.219389Z2nodeID://b5446189322024-03-29T22:03:08.219389Z2nodeID://b5446174182024-03-29T22:03:08.219389Z3nodeID://b5446170992024-03-29T22:03:08.219389Z3nodeID://b5446180082024-03-29T22:03:08.219389Z2nodeID://b5446189162024-03-29T22:03:08.219389Z2nodeID://b5446181202024-03-29T22:03:08.219389Z2nodeID://b5446169242024-03-29T22:03:08.219389Z4nodeID://b5446178762024-03-29T22:03:08.219389Z2nodeID://b5446175142024-03-29T22:03:08.219389Z2nodeID://b5446171952024-03-29T22:03:08.219389Z3nodeID://b5446184662024-03-29T22:03:08.219389Z2nodeID://b5446169082024-03-29T22:03:08.219389Z4nodeID://b5446170642024-03-29T22:03:08.219389Z3nodeID://b5446179722024-03-29T22:03:08.219389Z2nodeID://b5446176102024-03-29T22:03:08.219389Z2nodeID://b5446164582024-03-29T22:03:08.219389Z9nodeID://b5446185622024-03-29T22:03:08.219389Z2nodeID://b5446177292024-03-29T22:03:08.219389Z2nodeID://b5446165702024-03-29T22:03:08.219389Z7nodeID://b5446170482024-03-29T22:03:08.219389Z3nodeID://b5446183192024-03-29T22:03:08.219389Z2nodeID://b5446171602024-03-29T22:03:08.219389Z3nodeID://b5446184312024-03-29T22:03:08.219389Z2nodeID://b287419012024-03-29T22:03:08.219389ZintroductionnodeID://b5446165542024-03-29T22:03:08.219389Z7nodeID://b5446178252024-03-29T22:03:08.219389Z2nodeID://b5446187772024-03-29T22:03:08.219389Z2nodeID://b5446164232024-03-29T22:03:08.219389Z11nodeID://b5446184152024-03-29T22:03:08.219389Z2nodeID://b5446180962024-03-29T22:03:08.219389Z2nodeID://b5446170132024-03-29T22:03:08.219389Z3nodeID://b5446179212024-03-29T22:03:08.219389Z2nodeID://b5446164072024-03-29T22:03:08.219389Z12nodeID://b5446167692024-03-29T22:03:08.219389Z4nodeID://b5446188732024-03-29T22:03:08.219389Z2nodeID://b5446173592024-03-29T22:03:08.219389Z3nodeID://b5446174712024-03-29T22:03:08.219389Z2nodeID://b5446180612024-03-29T22:03:08.219389Z2nodeID://b5446168652024-03-29T22:03:08.219389Z4nodeID://b5446174552024-03-29T22:03:08.219389Z3nodeID://b5446187262024-03-29T22:03:08.219389Z2nodeID://b5446173242024-03-29T22:03:08.219389Z3nodeID://b5446169612024-03-29T22:03:08.219389Z4nodeID://b5446167182024-03-29T22:03:08.219389Z5nodeID://b5446188222024-03-29T22:03:08.219389Z2nodeID://b5446168302024-03-29T22:03:08.219389Z4nodeID://b5446163992024-03-29T22:03:08.219389Z13nodeID://b5446173082024-03-29T22:03:08.219389Z3nodeID://b5446174202024-03-29T22:03:08.219389Z3nodeID://b5446183722024-03-29T22:03:08.219389Z2nodeID://b5446180102024-03-29T22:03:08.219389Z2nodeID://b5446168142024-03-29T22:03:08.219389Z4nodeID://b5446164952024-03-29T22:03:08.219389Z8nodeID://b5446181292024-03-29T22:03:08.219389Z2nodeID://b5446177662024-03-29T22:03:08.219389Z2nodeID://b5446183562024-03-29T22:03:08.219389Z2nodeID://b5446163642024-03-29T22:03:08.219389Z19nodeID://b5446182252024-03-29T22:03:08.219389Z2nodeID://b5446178622024-03-29T22:03:08.219389Z2nodeID://b5446163482024-03-29T22:03:08.219389Z38nodeID://b5446176192024-03-29T22:03:08.219389Z2nodeID://b5446164602024-03-29T22:03:08.219389Z9nodeID://b5446177312024-03-29T22:03:08.219389Z2nodeID://b5446183212024-03-29T22:03:08.219389Z2nodeID://b5446171692024-03-29T22:03:08.219389Z3nodeID://b5446177152024-03-29T22:03:08.219389Z2nodeID://b5446186672024-03-29T22:03:08.219389Z2nodeID://b5446172652024-03-29T22:03:08.219389Z3nodeID://b5446166592024-03-29T22:03:08.219389Z5nodeID://b5446187632024-03-29T22:03:08.219389Z2nodeID://b5446167712024-03-29T22:03:08.219389Z4nodeID://b5446173612024-03-29T22:03:08.219389Z3nodeID://b5446186322024-03-29T22:03:08.219389Z2nodeID://b5446171182024-03-29T22:03:08.219389Z3nodeID://b5446167552024-03-29T22:03:08.219389Z5nodeID://b5446172302024-03-29T22:03:08.219389Z3nodeID://b5446186162024-03-29T22:03:08.219389Z2nodeID://b5446166242024-03-29T22:03:08.219389Z6nodeID://b5446175762024-03-29T22:03:08.219389Z2nodeID://b5446172142024-03-29T22:03:08.219389Z3nodeID://b5446181662024-03-29T22:03:08.219389Z2nodeID://b5446167202024-03-29T22:03:08.219389Z5nodeID://b5446176722024-03-29T22:03:08.219389Z2nodeID://b5446182622024-03-29T22:03:08.219389Z2nodeID://b5446174292024-03-29T22:03:08.219389Z3nodeID://b5446180192024-03-29T22:03:08.219389Z2nodeID://b5446189272024-03-29T22:03:08.219389Z2nodeID://b5446181312024-03-29T22:03:08.219389Z2nodeID://b5446175252024-03-29T22:03:08.219389Z2nodeID://b5446184772024-03-29T22:03:08.219389Z2nodeID://b5446169192024-03-29T22:03:08.219389Z4nodeID://b5446181152024-03-29T22:03:08.219389Z2nodeID://b5446176212024-03-29T22:03:08.219389Z2nodeID://b5446164692024-03-29T22:03:08.21938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datanodeID://b5446173672024-03-29T22:03:08.219389Z3nodeID://b5446186382024-03-29T22:03:08.219389Z2nodeID://b5446172362024-03-29T22:03:08.219389Z3nodeID://b5446168732024-03-29T22:03:08.219389Z4nodeID://b5446187342024-03-29T22:03:08.219389Z2nodeID://b5446173322024-03-29T22:03:08.219389Z3nodeID://b5446182842024-03-29T22:03:08.219389Z2nodeID://b5446167262024-03-29T22:03:08.219389Z5nodeID://b5446188302024-03-29T22:03:08.219389Z2nodeID://b5446176782024-03-29T22:03:08.219389Z2nodeID://b5446182682024-03-29T22:03:08.219389Z2nodeID://b5446183802024-03-29T22:03:08.219389Z2nodeID://b5446168222024-03-29T22:03:08.219389Z4nodeID://b5446177742024-03-29T22:03:08.219389Z2nodeID://b5446181372024-03-29T22:03:08.219389Z2nodeID://b5446163722024-03-29T22:03:08.219389Z17nodeID://b5446176432024-03-29T22:03:08.219389Z2nodeID://b5446182332024-03-29T22:03:08.219389Z2nodeID://b5446178702024-03-29T22:03:08.219389Z2nodeID://b5446179892024-03-29T22:03:08.219389Z2nodeID://b5446176272024-03-29T22:03:08.219389Z2nodeID://b5446185792024-03-29T22:03:08.219389Z2nodeID://b287419272024-03-29T22:03:08.219389ZCollectively, our findings provide key insights into the leukemogenic process in human AML and confirm historical predictions from early clonality studies of the existence of a pre-leukemic state3,>>37<<.nodeID://b5446186912024-03-29T22:03:08.219389Z2nodeID://b5446171772024-03-29T22:03:08.219389Z3nodeID://b5446186752024-03-29T22:03:08.219389Z2nodeID://b5446166832024-03-29T22:03:08.219389Z5nodeID://b5446172732024-03-29T22:03:08.219389Z3nodeID://b5446185442024-03-29T22:03:08.219389Z2nodeID://b5446166672024-03-29T22:03:08.219389Z5nodeID://b5446179382024-03-29T22:03:08.219389Z2nodeID://b5446185282024-03-29T22:03:08.219389Z2nodeID://b5446165362024-03-29T22:03:08.219389Z7nodeID://b5446186402024-03-29T22:03:08.219389Z2nodeID://b5446171262024-03-29T22:03:08.219389Z3nodeID://b5446180782024-03-29T22:03:08.219389Z2nodeID://b5446166322024-03-29T22:03:08.219389Z6nodeID://b5446179032024-03-29T22:03:08.219389Z2nodeID://b5446175842024-03-29T22:03:08.219389Z2nodeID://b5446172222024-03-29T22:03:08.219389Z3nodeID://b5446169782024-03-29T22:03:08.219389Z3nodeID://b5446181742024-03-29T22:03:08.219389Z2nodeID://b5446175682024-03-29T22:03:08.219389Z2nodeID://b5446188392024-03-29T22:03:08.219389Z2nodeID://b5446176802024-03-29T22:03:08.219389Z2nodeID://b5446182702024-03-29T22:03:08.219389Z2nodeID://b5446174372024-03-29T22:03:08.219389Z3nodeID://b5446180272024-03-29T22:03:08.219389Z2nodeID://b5446169432024-03-29T22:03:08.219389Z4nodeID://b5446175332024-03-29T22:03:08.219389Z2nodeID://b5446188042024-03-29T22:03:08.219389Z2nodeID://b5446184852024-03-29T22:03:08.219389Z2nodeID://b5446169272024-03-29T22:03:08.219389Z4nodeID://b5446181232024-03-29T22:03:08.219389Z2nodeID://b5446170832024-03-29T22:03:08.219389Z3nodeID://b5446178792024-03-29T22:03:08.219389Z2nodeID://b5446179912024-03-29T22:03:08.219389Z2nodeID://b5446189002024-03-29T22:03:08.219389Z2nodeID://b5446164772024-03-29T22:03:08.219389Z9nodeID://b5446184692024-03-29T22:03:08.219389Z2nodeID://b5446185812024-03-29T22:03:08.219389Z2nodeID://b287419162024-03-29T22:03:08.219389ZInsight into the phenotype of the normal cell from which clonal expansion can initiate was first provided by the pioneering studies of Fialkow in CML, which demonstrated that BCR-ABL1 arises in a multipotential HSC>>25<<. However, for the majority of AML cases that arise de novo without any prior clinical perturbations, insight into the cellular context and functional consequences of the earliest genetic lesions requires identification and examination ofnodeID://b5446170672024-03-29T22:03:08.219389Z3nodeID://b5446183382024-03-29T22:03:08.219389Z2nodeID://b5446179752024-03-29T22:03:08.219389Z2nodeID://b5446165732024-03-29T22:03:08.219389Z7nodeID://b5446178442024-03-29T22:03:08.219389Z2nodeID://b5446184342024-03-29T22:03:08.219389Z2nodeID://b5446170322024-03-29T22:03:08.219389Z3nodeID://b5446178282024-03-29T22:03:08.219389Z2nodeID://b5446179402024-03-29T22:03:08.219389Z2nodeID://b5446164262024-03-29T22:03:08.219389Z11nodeID://b5446185302024-03-29T22:03:08.219389Z2nodeID://b5446188922024-03-29T22:03:08.219389Z2nodeID://b5446173782024-03-29T22:03:08.219389Z3nodeID://b5446186492024-03-29T22:03:08.219389Z2nodeID://b5446188762024-03-29T22:03:08.219389Z2nodeID://b5446168842024-03-29T22:03:08.219389Z4nodeID://b5446165222024-03-29T22:03:08.219389Z7nodeID://b5446180802024-03-29T22:03:08.219389Z2nodeID://b5446174742024-03-29T22:03:08.219389Z2nodeID://b5446187452024-03-29T22:03:08.219389Z2nodeID://b5446168682024-03-29T22:03:08.219389Z4nodeID://b5446169802024-03-29T22:03:08.219389Z3nodeID://b5446173432024-03-29T22:03:08.219389Z3nodeID://b5446175702024-03-29T22:03:08.219389Z2nodeID://b5446167372024-03-29T22:03:08.219389Z5nodeID://b287419422024-03-29T22:03:08.219389ZPrior studies in T-ALL46 and B-ALL7,11,14 revealed the existence of genetically diverse subclones at diagnosis. As found originally in these diseases>>47<< and now in AML, in approximately 50% of patients the relapse clone is not related to the predominant clone at diagnosis but rather to a minor leukemic subclone 10,15 or to a predicted ancestral clone47, Our direct demonstration thatnodeID://b5446188412024-03-29T22:03:08.219389Z2nodeID://b5446176892024-03-29T22:03:08.219389Z2nodeID://b5446173272024-03-29T22:03:08.219389Z3nodeID://b5446182792024-03-29T22:03:08.219389Z2nodeID://b5446183912024-03-29T22:03:08.219389Z2nodeID://b5446168332024-03-29T22:03:08.219389Z4nodeID://b5446177852024-03-29T22:03:08.219389Z2nodeID://b5446183752024-03-29T22:03:08.219389Z2nodeID://b5446163832024-03-29T22:03:08.219389Z15nodeID://b5446182442024-03-29T22:03:08.219389Z2nodeID://b5446178812024-03-29T22:03:08.219389Z2nodeID://b5446163672024-03-29T22:03:08.219389Z17nodeID://b5446176382024-03-29T22:03:08.219389Z2nodeID://b5446189092024-03-29T22:03:08.219389Z2nodeID://b5446182282024-03-29T22:03:08.219389Z2nodeID://b5446183402024-03-29T22:03:08.219389Z2nodeID://b5446177342024-03-29T22:03:08.219389Z2nodeID://b5446186862024-03-29T22:03:08.219389Z2nodeID://b5446176032024-03-29T22:03:08.219389Z2nodeID://b5446172842024-03-29T22:03:08.219389Z3nodeID://b5446178302024-03-29T22:03:08.219389Z2nodeID://b5446166782024-03-29T22:03:08.219389Z5nodeID://b5446187822024-03-29T22:03:08.219389Z2nodeID://b5446179492024-03-29T22:03:08.219389Z2nodeID://b5446172682024-03-29T22:03:08.219389Z3nodeID://b5446185392024-03-29T22:03:08.219389Z2nodeID://b5446173802024-03-29T22:03:08.219389Z3nodeID://b287419232024-03-29T22:03:08.219389Zarising earlier in leukemogenesis than NPM1c and FLT3-ITD, a conclusion predicted from recent studies on bulk AML blasts showing that NPM1c and FLT3-ITD occur late and are the only genes recurrently mutated in DNMT3amut AML15,28,>>32<<. Moreover, our findings establish that DNMT3amut occurs in an ancestral cell that gives rise to both T-cells and the dominant AML clone present at diagnosis.nodeID://b5446186512024-03-29T22:03:08.219389Z2nodeID://b5446167742024-03-29T22:03:08.219389Z4nodeID://b5446171372024-03-29T22:03:08.219389Z3nodeID://b5446180892024-03-29T22:03:08.219389Z2nodeID://b5446186352024-03-29T22:03:08.219389Z2nodeID://b5446166432024-03-29T22:03:08.219389Z6nodeID://b5446172332024-03-29T22:03:08.219389Z3nodeID://b5446185042024-03-29T22:03:08.219389Z2nodeID://b5446169892024-03-29T22:03:08.219389Z3nodeID://b5446166272024-03-29T22:03:08.219389Z6nodeID://b5446181852024-03-29T22:03:08.219389Z2nodeID://b5446175792024-03-29T22:03:08.219389Z2nodeID://b5446176912024-03-29T22:03:08.219389Z2nodeID://b5446186002024-03-29T22:03:08.219389Z2nodeID://b5446182812024-03-29T22:03:08.219389Z2nodeID://b5446180382024-03-29T22:03:08.219389Z2nodeID://b5446176752024-03-29T22:03:08.219389Z2nodeID://b5446175442024-03-29T22:03:08.219389Z2nodeID://b5446181342024-03-29T22:03:08.219389Z2nodeID://b5446169382024-03-29T22:03:08.219389Z4nodeID://b5446175282024-03-29T22:03:08.219389Z2nodeID://b5446176402024-03-29T22:03:08.219389Z2nodeID://b5446180032024-03-29T22:03:08.219389Z2nodeID://b5446189112024-03-29T22:03:08.219389Z2nodeID://b5446185922024-03-29T22:03:08.219389Z2nodeID://b5446182302024-03-29T22:03:08.219389Z2nodeID://b5446170782024-03-29T22:03:08.219389Z3nodeID://b5446183492024-03-29T22:03:08.219389Z2nodeID://b5446179862024-03-29T22:03:08.219389Z2nodeID://b5446169032024-03-29T22:03:08.219389Z4nodeID://b5446185762024-03-29T22:03:08.219389Z2nodeID://b5446165842024-03-29T22:03:08.219389Z6nodeID://b5446171742024-03-29T22:03:08.219389Z3nodeID://b5446184452024-03-29T22:03:08.219389Z2nodeID://b5446165682024-03-29T22:03:08.219389Z7nodeID://b5446170432024-03-29T22:03:08.219389Z3nodeID://b5446178392024-03-29T22:03:08.219389Z2nodeID://b5446166802024-03-29T22:03:08.219389Z5nodeID://b5446179512024-03-29T22:03:08.219389Z2nodeID://b5446164372024-03-29T22:03:08.219389Z10nodeID://b5446172702024-03-29T22:03:08.219389Z3nodeID://b5446185412024-03-29T22:03:08.219389Z2nodeID://b287419122024-03-29T22:03:08.219389Zthese fundamental questions, due to the depth of our understanding of normal hematopoiesis and the availability of functional assays and analytic tools that allow examination of phenotypically defined populations at the single cell level>>21<<. In AML, a subset of cases evolve from a preceding clinically overt phase such as MDS or chronic myeloid leukemia (CML), characterized by clonal expansion of one or more blood 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is the number of mice with multilineage human grafts containing both CD33+ myeloid cells and CD33−CD19+ cells. The frequency of pre-leukaemic HSCs was calculated using the ELDA platform>>49<<.nodeID://b5446177162024-03-29T22:03:08.219389Z2nodeID://b5446173972024-03-29T22:03:08.219389Z3nodeID://b5446170352024-03-29T22:03:08.219389Z3nodeID://b5446183062024-03-29T22:03:08.219389Z2nodeID://b5446179432024-03-29T22:03:08.219389Z2nodeID://b5446188952024-03-29T22:03:08.219389Z2nodeID://b5446165412024-03-29T22:03:08.219389Z7nodeID://b5446178122024-03-29T22:03:08.219389Z2nodeID://b5446174932024-03-29T22:03:08.219389Z2nodeID://b5446187642024-03-29T22:03:08.219389Z2nodeID://b5446164102024-03-29T22:03:08.219389Z12nodeID://b5446184022024-03-29T22:03:08.219389Z2nodeID://b5446180832024-03-29T22:03:08.219389Z2nodeID://b5446168872024-03-29T22:03:08.219389Z4nodeID://b5446170002024-03-29T22:03:08.219389Z3nodeID://b5446167562024-03-29T22:03:08.219389Z5nodeID://b5446187482024-03-29T22:03:08.219389Z2nodeID://b5446188602024-03-29T22:03:08.219389Z2nodeID://b5446173462024-03-29T22:03:08.219389Z3nodeID://b5446186172024-03-29T22:03:08.219389Z2nodeID://b5446182982024-03-29T22:03:08.219389Z2nodeID://b5446168522024-03-29T22:03:08.219389Z4nodeID://b5446174422024-03-29T22:03:08.219389Z3nodeID://b5446166092024-03-29T22:03:08.219389Z6nodeID://b5446187132024-03-29T22:03:08.219389Z2nodeID://b5446183942024-03-29T22:03:08.219389Z2nodeID://b5446173112024-03-29T22:03:08.219389Z3nodeID://b5446177882024-03-29T22:03:08.219389Z2nodeID://b5446167052024-03-29T22:03:08.219389Z5nodeID://b5446163862024-03-29T22:03:08.219389Z14nodeID://b5446176572024-03-29T22:03:08.219389Z2nodeID://b5446184902024-03-29T22:03:08.219389Z2nodeID://b5446182472024-03-29T22:03:08.219389Z2nodeID://b5446168012024-03-29T22:03:08.219389Z4nodeID://b5446164822024-03-29T22:03:08.219389Z8nodeID://b5446181162024-03-29T22:03:08.219389Z2nodeID://b5446177532024-03-29T22:03:08.219389Z2nodeID://b5446183432024-03-29T22:03:08.219389Z2nodeID://b5446163512024-03-29T22:03:08.219389Z34nodeID://b5446182122024-03-29T22:03:08.219389Z2nodeID://b5446186892024-03-29T22:03:08.219389Z2nodeID://b5446166972024-03-29T22:03:08.219389Z5nodeID://b287419382024-03-29T22:03:08.219389ZPrior studies in T-ALL>>46<< and B-ALL7,11,14 revealed the existence of genetically diverse subclones at diagnosis.nodeID://b5446176062024-03-29T22:03:08.219389Z2nodeID://b5446172872024-03-29T22:03:08.219389Z3nodeID://b5446185582024-03-29T22:03:08.219389Z2nodeID://b5446167932024-03-29T22:03:08.219389Z4nodeID://b5446171562024-03-29T22:03:08.219389Z3nodeID://b5446177022024-03-29T22:03:08.219389Z2nodeID://b5446173832024-03-29T22:03:08.219389Z3nodeID://b5446186542024-03-29T22:03:08.219389Z2nodeID://b5446172522024-03-29T22:03:08.219389Z3nodeID://b5446170092024-03-29T22:03:08.219389Z3nodeID://b5446166462024-03-29T22:03:08.219389Z5nodeID://b5446187502024-03-29T22:03:08.219389Z2nodeID://b5446179172024-03-29T22:03:08.219389Z2nodeID://b5446175982024-03-29T22:03:08.219389Z2nodeID://b5446185072024-03-29T22:03:08.219389Z2nodeID://b5446181882024-03-29T22:03:08.219389Z2nodeID://b5446171052024-03-29T22:03:08.219389Z3nodeID://b5446167422024-03-29T22:03:08.219389Z5nodeID://b5446176942024-03-29T22:03:08.219389Z2nodeID://b5446180572024-03-29T22:03:08.219389Z2nodeID://b5446186032024-03-29T22:03:08.219389Z2nodeID://b5446166112024-03-29T22:03:08.219389Z6nodeID://b5446172012024-03-29T22:03:08.219389Z3nodeID://b5446169572024-03-29T22:03:08.219389Z4nodeID://b5446177902024-03-29T22:03:08.219389Z2nodeID://b5446181532024-03-29T22:03:08.219389Z2nodeID://b5446175472024-03-29T22:03:08.219389Z2nodeID://b5446188182024-03-29T22:03:08.219389Z2nodeID://b5446184992024-03-29T22:03:08.219389Z2nodeID://b287419192024-03-29T22:03:08.219389ZConsistent with mutant allele frequencies reported in recent studies>>28<< DNMT3amut was found in 4 of 12 samples (mutant allele frequency ~50%) (Fig.nodeID://b5446174162024-03-29T22:03:08.219389Z3nodeID://b5446170972024-03-29T22:03:08.219389Z3nodeID://b5446180062024-03-29T22:03:08.219389Z2nodeID://b5446189142024-03-29T22:03:08.219389Z2nodeID://b5446185952024-03-29T22:03:08.219389Z2nodeID://b5446175122024-03-29T22:03:08.219389Z2nodeID://b5446171932024-03-29T22:03:08.219389Z3nodeID://b5446184642024-03-29T22:03:08.219389Z2nodeID://b5446169062024-03-29T22:03:08.219389Z4nodeID://b5446181022024-03-29T22:03:08.219389Z2nodeID://b5446165872024-03-29T22:03:08.219389Z6nodeID://b5446178582024-03-29T22:03:08.219389Z2nodeID://b5446184482024-03-29T22:03:08.219389Z2nodeID://b5446164562024-03-29T22:03:08.219389Z9nodeID://b5446185602024-03-29T22:03:08.219389Z2nodeID://b5446170462024-03-29T22:03:08.219389Z3nodeID://b5446183172024-03-29T22:03:08.219389Z2nodeID://b5446179542024-03-29T22:03:08.219389Z2nodeID://b5446165522024-03-29T22:03:08.219389Z7nodeID://b5446178232024-03-29T22:03:08.219389Z2nodeID://b5446171422024-03-29T22:03:08.219389Z3nodeID://b5446184132024-03-29T22:03:08.219389Z2nodeID://b5446168982024-03-29T22:03:08.219389Z4nodeID://b5446180942024-03-29T22:03:08.219389Z2nodeID://b5446170112024-03-29T22:03:08.219389Z3nodeID://b5446178072024-03-29T22:03:08.219389Z2nodeID://b5446174882024-03-29T22:03:08.219389Z2nodeID://b5446164052024-03-29T22:03:08.219389Z12nodeID://b5446187592024-03-29T22:03:08.219389Z2nodeID://b287419452024-03-29T22:03:08.219389Zfound originally in these diseases47 and now in AML, in approximately 50% of patients the relapse clone is not related to the predominant clone at diagnosis but rather to a minor leukemic subclone 10,15 or to a predicted ancestral clone>>47<<, Our direct demonstration that ancestral clones persist at remission suggests that preL-HSCs are resistant to induction chemotherapy and for some patients they might represent a reservoir from which relapse arises.nodeID://b5446188712024-03-29T22:03:08.219389Z2nodeID://b5446173572024-03-29T22:03:08.219389Z3nodeID://b5446181902024-03-29T22:03:08.219389Z2nodeID://b5446169942024-03-29T22:03:08.219389Z3nodeID://b5446188552024-03-29T22:03:08.219389Z2nodeID://b5446165012024-03-29T22:03:08.219389Z8nodeID://b5446168632024-03-29T22:03:08.219389Z4nodeID://b5446174532024-03-29T22:03:08.219389Z3nodeID://b5446187242024-03-29T22:03:08.219389Z2nodeID://b5446180432024-03-29T22:03:08.219389Z2nodeID://b5446168472024-03-29T22:03:08.219389Z4nodeID://b5446177992024-03-29T22:03:08.219389Z2nodeID://b5446187082024-03-29T22:03:08.219389Z2nodeID://b5446167162024-03-29T22:03:08.219389Z5nodeID://b5446188202024-03-29T22:03:08.219389Z2nodeID://b5446163972024-03-29T22:03:08.219389Z13nodeID://b5446183892024-03-29T22:03:08.219389Z2nodeID://b287419082024-03-29T22:03:08.219389ZEarly and possibly initiating mutations have been identified from analysis of pre-neoplastic lesions in breast16, lung>>17<<, skin18, and colon cancer19, as well as from studies of AML cases that evolved from a prior myelodysplastic syndrome (MDS)20.nodeID://b5446173062024-03-29T22:03:08.219389Z3nodeID://b5446182582024-03-29T22:03:08.219389Z2nodeID://b5446178952024-03-29T22:03:08.219389Z2nodeID://b5446168122024-03-29T22:03:08.219389Z4nodeID://b5446164932024-03-29T22:03:08.219389Z8nodeID://b5446177642024-03-29T22:03:08.219389Z2nodeID://b5446174022024-03-29T22:03:08.219389Z3nodeID://b5446183542024-03-29T22:03:08.219389Z2nodeID://b5446177482024-03-29T22:03:08.219389Z2nodeID://b5446178602024-03-29T22:03:08.219389Z2nodeID://b5446163462024-03-29T22:03:08.219389Z44nodeID://b5446184502024-03-29T22:03:08.219389Z2nodeID://b5446176172024-03-29T22:03:08.219389Z2nodeID://b5446172982024-03-29T22:03:08.219389Z3nodeID://b5446182072024-03-29T22:03:08.219389Z2nodeID://b5446164422024-03-29T22:03:08.219389Z10nodeID://b5446187962024-03-29T22:03:08.219389Z2nodeID://b5446177132024-03-29T22:03:08.219389Z2nodeID://b5446173942024-03-29T22:03:08.219389Z3nodeID://b5446183032024-03-29T22:03:08.219389Z2nodeID://b5446186652024-03-29T22:03:08.219389Z2nodeID://b5446167882024-03-29T22:03:08.219389Z4nodeID://b5446172632024-03-29T22:03:08.219389Z3nodeID://b5446166572024-03-29T22:03:08.219389Z5nodeID://b5446174902024-03-29T22:03:08.219389Z2nodeID://b287419342024-03-29T22:03:08.219389ZPre-leukemic progenitors of varying phenotypes have been reported in other types of hematologic malignancies>>25<<,39–41, although functional studies were limited.nodeID://b5446187612024-03-29T22:03:08.219389Z2nodeID://b5446172472024-03-29T22:03:08.219389Z3nodeID://b5446185182024-03-29T22:03:08.219389Z2nodeID://b5446181992024-03-29T22:03:08.219389Z2nodeID://b5446167532024-03-29T22:03:08.219389Z5nodeID://b5446171162024-03-29T22:03:08.219389Z3nodeID://b5446186142024-03-29T22:03:08.219389Z2nodeID://b5446182952024-03-29T22:03:08.219389Z2nodeID://b5446172122024-03-29T22:03:08.219389Z3nodeID://b5446181642024-03-29T22:03:08.219389Z2nodeID://b5446166062024-03-29T22:03:08.219389Z6nodeID://b5446187102024-03-29T22:03:08.219389Z2nodeID://b5446175582024-03-29T22:03:08.219389Z2nodeID://b5446188292024-03-29T22:03:08.219389Z2nodeID://b5446181482024-03-29T22:03:08.219389Z2nodeID://b5446182602024-03-29T22:03:08.219389Z2nodeID://b5446167022024-03-29T22:03:08.219389Z5nodeID://b5446180172024-03-29T22:03:08.219389Z2nodeID://b5446176542024-03-29T22:03:08.219389Z2nodeID://b5446189252024-03-29T22:03:08.219389Z2nodeID://b5446175232024-03-29T22:03:08.219389Z2nodeID://b5446181132024-03-29T22:03:08.219389Z2nodeID://b5446169172024-03-29T22:03:08.219389Z4nodeID://b5446177502024-03-29T22:03:08.219389Z2nodeID://b5446165982024-03-29T22:03:08.219389Z6nodeID://b5446175072024-03-29T22:03:08.219389Z2nodeID://b5446178692024-03-29T22:03:08.219389Z2nodeID://b5446171882024-03-29T22:03:08.219389Z3nodeID://b5446184592024-03-29T22:03:08.219389Z2nodeID://b287419152024-03-29T22:03:08.219389ZInterestingly, somatic mutations in some leukemia-associated genes such as TET2 have also been linked to multilineage clonal hematopoiesis in aging healthy individuals>>24<<. Insight into the phenotype of the normal cell from which clonal expansion can initiate was first provided by the pioneering studies of Fialkow in CML, which demonstrated that BCR-ABL1 arises in a multipotential HSC25. However, for thenodeID://b5446185712024-03-29T22:03:08.219389Z2nodeID://b5446166942024-03-29T22:03:08.219389Z5nodeID://b5446170572024-03-29T22:03:08.219389Z3nodeID://b5446179652024-03-29T22:03:08.219389Z2nodeID://b5446185552024-03-29T22:03:08.219389Z2nodeID://b5446165632024-03-29T22:03:08.219389Z7nodeID://b5446171532024-03-29T22:03:08.219389Z3nodeID://b5446167902024-03-29T22:03:08.219389Z4nodeID://b5446184242024-03-29T22:03:08.219389Z2nodeID://b5446165472024-03-29T22:03:08.219389Z7nodeID://b5446178182024-03-29T22:03:08.219389Z2nodeID://b5446174992024-03-29T22:03:08.219389Z2nodeID://b5446164162024-03-29T22:03:08.219389Z11nodeID://b5446184082024-03-29T22:03:08.219389Z2nodeID://b5446185202024-03-29T22:03:08.219389Z2nodeID://b5446170062024-03-29T22:03:08.219389Z3nodeID://b5446179142024-03-29T22:03:08.219389Z2nodeID://b5446175952024-03-29T22:03:08.219389Z2nodeID://b5446188662024-03-29T22:03:08.219389Z2nodeID://b5446165122024-03-29T22:03:08.219389Z8nodeID://b5446174642024-03-29T22:03:08.219389Z3nodeID://b5446171022024-03-29T22:03:08.219389Z3nodeID://b5446180542024-03-29T22:03:08.219389Z2nodeID://b5446168582024-03-29T22:03:08.219389Z4nodeID://b5446174482024-03-29T22:03:08.219389Z3nodeID://b5446187192024-03-29T22:03:08.219389Z2nodeID://b5446175602024-03-29T22:03:08.219389Z2nodeID://b287419412024-03-29T22:03:08.219389ZPrior studies in T-ALL46 and B-ALL7,11,>>14<< revealed the existence of genetically diverse subclones at diagnosis.nodeID://b5446188312024-03-29T22:03:08.219389Z2nodeID://b5446169542024-03-29T22:03:08.219389Z4nodeID://b5446173172024-03-29T22:03:08.219389Z3nodeID://b5446181502024-03-29T22:03:08.219389Z2nodeID://b5446182692024-03-29T22:03:08.219389Z2nodeID://b5446188152024-03-29T22:03:08.219389Z2nodeID://b5446168232024-03-29T22:03:08.219389Z4nodeID://b5446184962024-03-29T22:03:08.219389Z2nodeID://b5446174132024-03-29T22:03:08.219389Z3nodeID://b5446170942024-03-29T22:03:08.219389Z3nodeID://b5446168072024-03-29T22:03:08.219389Z4nodeID://b5446183652024-03-29T22:03:08.219389Z2nodeID://b5446164882024-03-29T22:03:08.219389Z8nodeID://b5446177592024-03-29T22:03:08.219389Z2nodeID://b5446178712024-03-29T22:03:08.219389Z2nodeID://b5446163572024-03-29T22:03:08.219389Z23nodeID://b5446171902024-03-29T22:03:08.219389Z3nodeID://b287419042024-03-29T22:03:08.219389ZHowever the modern era of cancer genomics has exposed a more complex clonal architecture in many tumor types4, where multiple genetically distinct subclones co-exist with the dominant clone>>5<<,6. Comparison of diagnostic and recurrent/metastatic samples obtained from the same patient has established that the latter frequently do not evolve from the dominant clone, but instead can be traced either to a minor subclone present atnodeID://b5446184612024-03-29T22:03:08.219389Z2nodeID://b5446182182024-03-29T22:03:08.219389Z2nodeID://b5446178552024-03-29T22:03:08.219389Z2nodeID://b5446164532024-03-29T22:03:08.219389Z9nodeID://b5446177242024-03-29T22:03:08.219389Z2nodeID://b5446183142024-03-29T22:03:08.219389Z2nodeID://b5446167992024-03-29T22:03:08.219389Z4nodeID://b5446177082024-03-29T22:03:08.219389Z2nodeID://b5446178202024-03-29T22:03:08.219389Z2nodeID://b5446187722024-03-29T22:03:08.219389Z2nodeID://b5446184102024-03-29T22:03:08.219389Z2nodeID://b5446172582024-03-29T22:03:08.219389Z3nodeID://b5446168952024-03-29T22:03:08.219389Z4nodeID://b5446185292024-03-29T22:03:08.219389Z2nodeID://b5446167642024-03-29T22:03:08.219389Z5nodeID://b5446187562024-03-29T22:03:08.219389Z2nodeID://b5446164022024-03-29T22:03:08.219389Z12nodeID://b5446173542024-03-29T22:03:08.219389Z3nodeID://b5446186252024-03-29T22:03:08.219389Z2nodeID://b5446167482024-03-29T22:03:08.219389Z5nodeID://b5446172232024-03-29T22:03:08.219389Z3nodeID://b5446168602024-03-29T22:03:08.219389Z4nodeID://b5446166172024-03-29T22:03:08.219389Z6nodeID://b5446174502024-03-29T22:03:08.219389Z3nodeID://b5446187212024-03-29T22:03:08.219389Z2nodeID://b287419302024-03-29T22:03:08.219389ZmethodsnodeID://b5446172072024-03-29T22:03:08.219389Z3nodeID://b5446175692024-03-29T22:03:08.219389Z2nodeID://b5446181592024-03-29T22:03:08.219389Z2nodeID://b5446177962024-03-29T22:03:08.219389Z2nodeID://b5446167132024-03-29T22:03:08.219389Z5nodeID://b5446182712024-03-29T22:03:08.219389Z2nodeID://b5446163942024-03-29T22:03:08.219389Z13nodeID://b5446176652024-03-29T22:03:08.219389Z2nodeID://b5446182552024-03-29T22:03:08.219389Z2nodeID://b5446177612024-03-29T22:03:08.219389Z2nodeID://b5446181242024-03-29T22:03:08.219389Z2nodeID://b5446175182024-03-29T22:03:08.219389Z2nodeID://b5446171992024-03-29T22:03:08.219389Z3nodeID://b5446181082024-03-29T22:03:08.219389Z2nodeID://b5446182202024-03-29T22:03:08.219389Z2nodeID://b5446176142024-03-29T22:03:08.219389Z2nodeID://b5446172952024-03-29T22:03:08.219389Z3nodeID://b5446185662024-03-29T22:03:08.219389Z2nodeID://b5446171642024-03-29T22:03:08.219389Z3nodeID://b5446177102024-03-29T22:03:08.219389Z2nodeID://b5446165582024-03-29T22:03:08.219389Z7nodeID://b5446186622024-03-29T22:03:08.219389Z2nodeID://b5446166702024-03-29T22:03:08.219389Z5nodeID://b5446178292024-03-29T22:03:08.219389Z2nodeID://b5446171482024-03-29T22:03:08.219389Z3nodeID://b5446184192024-03-29T22:03:08.219389Z2nodeID://b5446172602024-03-29T22:03:08.219389Z3nodeID://b287419112024-03-29T22:03:08.219389Zand possibly initiating mutations have been identified from analysis of pre-neoplastic lesions in breast16, lung17, skin18, and colon cancer19, as well as from studies of AML cases that evolved from a prior myelodysplastic syndrome (MDS)>>20<<. However, key questions remain unanswered. In particular, can clinically relevant clones be traced back to a non-tumorigenic 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-03-29T22:03:08.219389Z2nodeID://b5446177272024-03-29T22:03:08.219389Z2nodeID://b5446186792024-03-29T22:03:08.219389Z2nodeID://b5446187912024-03-29T22:03:08.219389Z2nodeID://b287419372024-03-29T22:03:08.219389ZOur study is consistent with mouse studies showing that HSC lacking DNMT3a have a competitive growth advantage43,>>44<<, and with a recent report predicting that the human DNMT3amut results in loss of function45.nodeID://b5446172772024-03-29T22:03:08.219389Z3nodeID://b5446164212024-03-29T22:03:08.219389Z11nodeID://b5446167832024-03-29T22:03:08.219389Z4nodeID://b5446187752024-03-29T22:03:08.219389Z2nodeID://b5446173732024-03-29T22:03:08.219389Z3nodeID://b5446186442024-03-29T22:03:08.219389Z2nodeID://b5446167672024-03-29T22:03:08.219389Z5nodeID://b5446186282024-03-29T22:03:08.219389Z2nodeID://b5446166362024-03-29T22:03:08.219389Z6nodeID://b5446187402024-03-29T22:03:08.219389Z2nodeID://b5446172262024-03-29T22:03:08.219389Z3nodeID://b5446181782024-03-29T22:03:08.219389Z2nodeID://b5446167322024-03-29T22:03:08.219389Z5nodeID://b5446173222024-03-29T22:03:08.219389Z3nodeID://b5446176842024-03-29T22:03:08.219389Z2nodeID://b5446182742024-03-29T22:03:08.219389Z2nodeID://b5446176682024-03-29T22:03:08.219389Z2nodeID://b5446177802024-03-29T22:03:08.219389Z2nodeID://b5446183702024-03-29T22:03:08.219389Z2nodeID://b5446175372024-03-29T22:03:08.219389Z2nodeID://b5446181272024-03-29T22:03:08.219389Z2nodeID://b5446163622024-03-29T22:03:08.219389Z20nodeID://b5446176332024-03-29T22:03:08.219389Z2nodeID://b5446189042024-03-29T22:03:08.219389Z2nodeID://b5446185852024-03-29T22:03:08.219389Z2nodeID://b5446182232024-03-29T22:03:08.219389Z2nodeID://b5446179792024-03-29T22:03:08.219389Z2nodeID://b5446171832024-03-29T22:03:08.219389Z3nodeID://b5446185692024-03-29T22:03:08.219389Z2nodeID://b5446165772024-03-29T22:03:08.219389Z6nodeID://b287419262024-03-29T22:03:08.219389ZCollectively, our findings provide key insights into the leukemogenic process in human AML and confirm historical predictions from early clonality studies of the existence of a pre-leukemic state>>3<<,37.nodeID://b5446186812024-03-29T22:03:08.219389Z2nodeID://b5446171672024-03-29T22:03:08.219389Z3nodeID://b5446184382024-03-29T22:03:08.219389Z2nodeID://b5446170362024-03-29T22:03:08.219389Z3nodeID://b5446166732024-03-29T22:03:08.219389Z5nodeID://b5446179442024-03-29T22:03:08.219389Z2nodeID://b5446185342024-03-29T22:03:08.219389Z2nodeID://b5446179282024-03-29T22:03:08.219389Z2nodeID://b5446171322024-03-29T22:03:08.219389Z3nodeID://b5446165262024-03-29T22:03:08.219389Z7nodeID://b5446180842024-03-29T22:03:08.219389Z2nodeID://b5446186302024-03-29T22:03:08.219389Z2nodeID://b5446174782024-03-29T22:03:08.219389Z2nodeID://b5446180682024-03-29T22:03:08.219389Z2nodeID://b5446181802024-03-29T22:03:08.219389Z2nodeID://b5446169842024-03-29T22:03:08.219389Z3nodeID://b5446166222024-03-29T22:03:08.219389Z6nodeID://b5446175742024-03-29T22:03:08.219389Z2nodeID://b5446188452024-03-29T22:03:08.219389Z2nodeID://b5446169682024-03-29T22:03:08.219389Z4nodeID://b5446174432024-03-29T22:03:08.219389Z3nodeID://b5446180332024-03-29T22:03:08.219389Z2nodeID://b5446168372024-03-29T22:03:08.219389Z4nodeID://b5446176702024-03-29T22:03:08.219389Z2nodeID://b5446174272024-03-29T22:03:08.219389Z3nodeID://b5446177892024-03-29T22:03:08.219389Z2nodeID://b5446183792024-03-29T22:03:08.219389Z2nodeID://b5446184912024-03-29T22:03:08.219389Z2nodeID://b5446169332024-03-29T22:03:08.219389Z4nodeID://b287419072024-03-29T22:03:08.219389ZEarly and possibly initiating mutations have been identified from analysis of pre-neoplastic lesions in breast>>16<<, lung17, skin18, and colon cancer19, as well as from studies of AML cases that evolved from a prior myelodysplastic syndrome (MDS)20.nodeID://b5446178852024-03-29T22:03:08.219389Z2nodeID://b5446184752024-03-29T22:03:08.219389Z2nodeID://b5446164832024-03-29T22:03:08.219389Z8nodeID://b5446170732024-03-29T22:03:08.219389Z3nodeID://b5446179812024-03-29T22:03:08.219389Z2nodeID://b5446183442024-03-29T22:03:08.219389Z2nodeID://b5446164672024-03-29T22:03:08.219389Z9nodeID://b5446177382024-03-29T22:03:08.219389Z2nodeID://b5446183282024-03-29T22:03:08.219389Z2nodeID://b5446184402024-03-29T22:03:08.219389Z2nodeID://b5446178342024-03-29T22:03:08.219389Z2nodeID://b5446164322024-03-29T22:03:08.219389Z10nodeID://b5446187862024-03-29T22:03:08.219389Z2nodeID://b5446177032024-03-29T22:03:08.219389Z2nodeID://b5446170222024-03-29T22:03:08.219389Z3nodeID://b5446173842024-03-29T22:03:08.219389Z3nodeID://b5446179302024-03-29T22:03:08.219389Z2nodeID://b5446167782024-03-29T22:03:08.219389Z4nodeID://b5446188822024-03-29T22:03:08.219389Z2nodeID://b5446173682024-03-29T22:03:08.219389Z3nodeID://b5446186392024-03-29T22:03:08.219389Z2nodeID://b5446174802024-03-29T22:03:08.219389Z2nodeID://b5446187512024-03-29T22:03:08.219389Z2nodeID://b287419332024-03-29T22:03:08.219389ZdiscussionnodeID://b5446180702024-03-29T22:03:08.219389Z2nodeID://b5446168742024-03-29T22:03:08.219389Z4nodeID://b5446172372024-03-29T22:03:08.219389Z3nodeID://b5446181892024-03-29T22:03:08.219389Z2nodeID://b5446187352024-03-29T22:03:08.219389Z2nodeID://b5446167432024-03-29T22:03:08.219389Z5nodeID://b5446169702024-03-29T22:03:08.219389Z4nodeID://b5446173332024-03-29T22:03:08.219389Z3nodeID://b5446186042024-03-29T22:03:08.219389Z2nodeID://b5446182852024-03-29T22:03:08.219389Z2nodeID://b5446167272024-03-29T22:03:08.219389Z5nodeID://b5446176792024-03-29T22:03:08.219389Z2nodeID://b5446177912024-03-29T22:03:08.219389Z2nodeID://b5446187002024-03-29T22:03:08.219389Z2nodeID://b5446183812024-03-29T22:03:08.219389Z2nodeID://b5446177752024-03-29T22:03:08.219389Z2nodeID://b5446181382024-03-29T22:03:08.219389Z2nodeID://b5446163732024-03-29T22:03:08.219389Z17nodeID://b5446176442024-03-29T22:03:08.219389Z2nodeID://b5446182342024-03-29T22:03:08.219389Z2nodeID://b5446176282024-03-29T22:03:08.219389Z2nodeID://b5446181032024-03-29T22:03:08.219389Z2nodeID://b5446177402024-03-29T22:03:08.219389Z2nodeID://b5446186922024-03-29T22:03:08.219389Z2nodeID://b5446183302024-03-29T22:03:08.219389Z2nodeID://b5446171782024-03-29T22:03:08.219389Z3nodeID://b5446184492024-03-29T22:03:08.219389Z2nodeID://b5446186762024-03-29T22:03:08.219389Z2nodeID://b5446166842024-03-29T22:03:08.219389Z5nodeID://b5446172742024-03-29T22:03:08.219389Z3nodeID://b5446185452024-03-29T22:03:08.219389Z2nodeID://b5446166682024-03-29T22:03:08.219389Z5nodeID://b5446167802024-03-29T22:03:08.219389Z4nodeID://b5446171432024-03-29T22:03:08.219389Z3nodeID://b5446179392024-03-29T22:03:08.219389Z2nodeID://b5446173702024-03-29T22:03:08.219389Z3nodeID://b5446165372024-03-29T22:03:08.219389Z7nodeID://b287419222024-03-29T22:03:08.219389ZDNMT3amut arising earlier in leukemogenesis than NPM1c and FLT3-ITD, a conclusion predicted from recent studies on bulk AML blasts showing that NPM1c and FLT3-ITD occur late and are the only genes recurrently mutated in DNMT3amut AML15,>>28<<,32. Moreover, our findings establish that DNMT3amut occurs in an ancestral cell that gives rise to both T-cells and the dominant AML clone present at diagnosis.nodeID://b5446186412024-03-29T22:03:08.219389Z2nodeID://b5446171272024-03-29T22:03:08.219389Z3nodeID://b5446174892024-03-29T22:03:08.219389Z2nodeID://b5446180792024-03-29T22:03:08.219389Z2nodeID://b5446181912024-03-29T22:03:08.219389Z2nodeID://b5446166332024-03-29T22:03:08.219389Z6nodeID://b5446179042024-03-29T22:03:08.219389Z2nodeID://b5446175852024-03-29T22:03:08.219389Z2nodeID://b5446169792024-03-29T22:03:08.219389Z3nodeID://b5446181752024-03-29T22:03:08.219389Z2nodeID://b5446176812024-03-29T22:03:08.219389Z2nodeID://b5446180442024-03-29T22:03:08.219389Z2nodeID://b5446174382024-03-29T22:03:08.219389Z3nodeID://b5446187092024-03-29T22:03:08.219389Z2nodeID://b5446180282024-03-29T22:03:08.219389Z2nodeID://b5446181402024-03-29T22:03:08.219389Z2nodeID://b5446169442024-03-29T22:03:08.219389Z4nodeID://b5446175342024-03-29T22:03:08.219389Z2nodeID://b5446188052024-03-29T22:03:08.219389Z2nodeID://b5446184862024-03-29T22:03:08.219389Z2nodeID://b5446169282024-03-29T22:03:08.219389Z4nodeID://b5446174032024-03-29T22:03:08.219389Z3nodeID://b5446170842024-03-29T22:03:08.219389Z3nodeID://b5446179922024-03-29T22:03:08.219389Z2nodeID://b5446176302024-03-29T22:03:08.219389Z2nodeID://b5446189012024-03-29T22:03:08.219389Z2nodeID://b5446164782024-03-29T22:03:08.219389Z9nodeID://b5446185822024-03-29T22:03:08.219389Z2nodeID://b5446165902024-03-29T22:03:08.219389Z6nodeID://b5446177492024-03-29T22:03:08.219389Z2nodeID://b5446170682024-03-29T22:03:08.219389Z3nodeID://b5446183392024-03-29T22:03:08.219389Z2nodeID://b5446171802024-03-29T22:03:08.219389Z3nodeID://b5446179762024-03-29T22:03:08.219389Z2nodeID://b5446184512024-03-29T22:03:08.219389Z2nodeID://b287419032024-03-29T22:03:08.219389ZHowever the modern era of cancer genomics has exposed a more complex clonal architecture in many tumor types>>4<<, where multiple genetically distinct subclones co-exist with the dominant 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from 50% mutant allele frequency may be stochastic>>51<<, related to clonal heterogeneity, or due to the presence of copy number variations, for example loss of the wild type allele (loss of heterozygosity) or amplification of the mutant allele.nodeID://b5446177062024-03-29T22:03:08.219389Z2nodeID://b5446173872024-03-29T22:03:08.219389Z3nodeID://b5446186582024-03-29T22:03:08.219389Z2nodeID://b5446172562024-03-29T22:03:08.219389Z3nodeID://b5446168932024-03-29T22:03:08.219389Z4nodeID://b5446178022024-03-29T22:03:08.219389Z2nodeID://b5446174832024-03-29T22:03:08.219389Z2nodeID://b5446187542024-03-29T22:03:08.219389Z2nodeID://b5446164002024-03-29T22:03:08.219389Z13nodeID://b5446173522024-03-29T22:03:08.219389Z3nodeID://b5446171092024-03-29T22:03:08.219389Z3nodeID://b5446167462024-03-29T22:03:08.219389Z5nodeID://b5446188502024-03-29T22:03:08.219389Z2nodeID://b5446176982024-03-29T22:03:08.219389Z2nodeID://b5446186072024-03-29T22:03:08.219389Z2nodeID://b5446182882024-03-29T22:03:08.219389Z2nodeID://b5446172052024-03-29T22:03:08.219389Z3nodeID://b5446168422024-03-29T22:03:08.219389Z4nodeID://b5446177942024-03-29T22:03:08.219389Z2nodeID://b5446181572024-03-29T22:03:08.219389Z2nodeID://b5446187032024-03-29T22:03:08.219389Z2nodeID://b5446167112024-03-29T22:03:08.219389Z5nodeID://b5446163922024-03-29T22:03:08.219389Z13nodeID://b5446173012024-03-29T22:03:08.219389Z3nodeID://b5446182532024-03-29T22:03:08.219389Z2nodeID://b5446178902024-03-29T22:03:08.219389Z2nodeID://b5446176472024-03-29T22:03:08.219389Z2nodeID://b5446189182024-03-29T22:03:08.219389Z2nodeID://b5446185992024-03-29T22:03:08.219389Z2nodeID://b287419292024-03-29T22:03:08.219389Z3a and data not shown), consistent with a higher LSC frequency at relapse compared to diagnosis>>38<<. Together, these data provide evidence that DNMT3amut occurs in HSC/MPP capable of generating a long-term multilineage lympho-myeloid graft, confirming their designation as pre-leukemic HSC26 (preL-HSC). DNMT3amut also endows preL-HSCnodeID://b5446175162024-03-29T22:03:08.219389Z2nodeID://b5446171972024-03-29T22:03:08.219389Z3nodeID://b5446181062024-03-29T22:03:08.219389Z2nodeID://b5446186952024-03-29T22:03:08.219389Z2nodeID://b5446163412024-03-29T22:03:08.219389Z72nodeID://b5446176122024-03-29T22:03:08.219389Z2nodeID://b5446172932024-03-29T22:03:08.219389Z3nodeID://b5446185642024-03-29T22:03:08.219389Z2nodeID://b5446182022024-03-29T22:03:08.219389Z2nodeID://b5446166872024-03-29T22:03:08.219389Z5nodeID://b5446179582024-03-29T22:03:08.219389Z2nodeID://b5446185482024-03-29T22:03:08.219389Z2nodeID://b5446165562024-03-29T22:03:08.219389Z7nodeID://b5446186602024-03-29T22:03:08.219389Z2nodeID://b5446171462024-03-29T22:03:08.219389Z3nodeID://b5446184172024-03-29T22:03:08.219389Z2nodeID://b5446180982024-03-29T22:03:08.219389Z2nodeID://b5446166522024-03-29T22:03:08.219389Z5nodeID://b5446179232024-03-29T22:03:08.219389Z2nodeID://b5446164092024-03-29T22:03:08.219389Z12nodeID://b5446172422024-03-29T22:03:08.219389Z3nodeID://b5446185132024-03-29T22:03:08.219389Z2nodeID://b5446169982024-03-29T22:03:08.219389Z3nodeID://b5446181942024-03-29T22:03:08.219389Z2nodeID://b5446179072024-03-29T22:03:08.219389Z2nodeID://b5446171112024-03-29T22:03:08.219389Z3nodeID://b5446175882024-03-29T22:03:08.219389Z2nodeID://b5446188592024-03-29T22:03:08.219389Z2nodeID://b5446165052024-03-29T22:03:08.219389Z8nodeID://b5446174572024-03-29T22:03:08.219389Z3nodeID://b5446182902024-03-29T22:03:08.219389Z2nodeID://b5446180472024-03-29T22:03:08.219389Z2nodeID://b5446166012024-03-29T22:03:08.219389Z6nodeID://b5446169632024-03-29T22:03:08.219389Z4nodeID://b5446175532024-03-29T22:03:08.219389Z2nodeID://b5446188242024-03-29T22:03:08.219389Z2nodeID://b5446181432024-03-29T22:03:08.219389Z2nodeID://b5446169472024-03-29T22:03:08.219389Z4nodeID://b5446178992024-03-29T22:03:08.219389Z2nodeID://b5446188082024-03-29T22:03:08.219389Z2nodeID://b5446180122024-03-29T22:03:08.219389Z2nodeID://b5446168162024-03-29T22:03:08.219389Z4nodeID://b5446189202024-03-29T22:03:08.219389Z2nodeID://b5446164972024-03-29T22:03:08.219389Z8nodeID://b5446184892024-03-29T22:03:08.219389Z2nodeID://b287419182024-03-29T22:03:08.219389ZresultsnodeID://b5446174062024-03-29T22:03:08.219389Z3nodeID://b5446170872024-03-29T22:03:08.219389Z3nodeID://b5446183582024-03-29T22:03:08.219389Z2nodeID://b5446179952024-03-29T22:03:08.219389Z2nodeID://b5446169122024-03-29T22:03:08.219389Z4nodeID://b5446165932024-03-29T22:03:08.219389Z6nodeID://b5446178642024-03-29T22:03:08.219389Z2nodeID://b5446175022024-03-29T22:03:08.219389Z2nodeID://b5446184542024-03-29T22:03:08.219389Z2nodeID://b5446170522024-03-29T22:03:08.219389Z3nodeID://b5446178482024-03-29T22:03:08.219389Z2nodeID://b5446179602024-03-29T22:03:08.219389Z2nodeID://b5446164462024-03-29T22:03:08.219389Z10nodeID://b5446185502024-03-29T22:03:08.219389Z2nodeID://b5446177172024-03-29T22:03:08.219389Z2nodeID://b5446173982024-03-29T22:03:08.219389Z3nodeID://b5446183072024-03-29T22:03:08.219389Z2nodeID://b5446165422024-03-29T22:03:08.219389Z7nodeID://b5446188962024-03-29T22:03:08.219389Z2nodeID://b5446178132024-03-29T22:03:08.219389Z2nodeID://b5446174942024-03-29T22:03:08.219389Z2nodeID://b5446187652024-03-29T22:03:08.219389Z2nodeID://b5446164112024-03-29T22:03:08.219389Z12nodeID://b5446184032024-03-29T22:03:08.219389Z2nodeID://b5446168882024-03-29T22:03:08.219389Z4nodeID://b5446173632024-03-29T22:03:08.219389Z3nodeID://b5446170012024-03-29T22:03:08.219389Z3nodeID://b5446187492024-03-29T22:03:08.219389Z2nodeID://b5446175902024-03-29T22:03:08.219389Z2nodeID://b5446167572024-03-29T22:03:08.219389Z5nodeID://b287419442024-03-29T22:03:08.219389ZAs found originally in these diseases47 and now in AML, in approximately 50% of patients the relapse clone is not related to the predominant clone at diagnosis but rather to a minor leukemic subclone 10,>>15<< or to a predicted ancestral clone47, Our direct demonstration that ancestral clones persist at remission suggests that preL-HSCs are resistant to induction chemotherapy and for some patients they might represent a reservoir from whichnodeID://b5446188612024-03-29T22:03:08.219389Z2nodeID://b5446173472024-03-29T22:03:08.219389Z3nodeID://b5446186182024-03-29T22:03:08.219389Z2nodeID://b5446182992024-03-29T22:03:08.219389Z2nodeID://b5446172162024-03-29T22:03:08.219389Z3nodeID://b5446168532024-03-29T22:03:08.219389Z4nodeID://b5446187142024-03-29T22:03:08.219389Z2nodeID://b5446183952024-03-29T22:03:08.219389Z2nodeID://b5446173122024-03-29T22:03:08.219389Z3nodeID://b5446182642024-03-29T22:03:08.219389Z2nodeID://b5446167062024-03-29T22:03:08.219389Z5nodeID://b5446163872024-03-29T22:03:08.219389Z14nodeID://b5446188102024-03-29T22:03:08.219389Z2nodeID://b5446176582024-03-29T22:03:08.219389Z2nodeID://b5446189292024-03-29T22:03:08.219389Z2nodeID://b5446182482024-03-29T22:03:08.219389Z2nodeID://b5446183602024-03-29T22:03:08.219389Z2nodeID://b5446168022024-03-29T22:03:08.219389Z4nodeID://b5446181172024-03-29T22:03:08.219389Z2nodeID://b5446177542024-03-29T22:03:08.219389Z2nodeID://b5446163522024-03-29T22:03:08.219389Z32nodeID://b5446176232024-03-29T22:03:08.219389Z2nodeID://b5446182132024-03-29T22:03:08.219389Z2nodeID://b5446178502024-03-29T22:03:08.219389Z2nodeID://b5446166982024-03-29T22:03:08.219389Z5nodeID://b5446176072024-03-29T22:03:08.219389Z2nodeID://b5446179692024-03-29T22:03:08.219389Z2nodeID://b5446172882024-03-29T22:03:08.219389Z3nodeID://b5446185592024-03-29T22:03:08.219389Z2nodeID://b287419252024-03-29T22:03:08.219389ZAlthough the clonal contribution that an individual normal HSC makes in humans is unknown, studies in higher primates estimated that single HSC provide approximately 0.5% clonal contribution during steady-state hematopoiesis>>36<<. Thus, the high DNMT3amut allele frequency in HSC/MPP points to their clonal expansion as compared to non-mutated HSC. In Patient #11, DNMT3amut was also present in all downstream progenitors at variable frequencies. The mean allelenodeID://b5446186712024-03-29T22:03:08.219389Z2nodeID://b5446171572024-03-29T22:03:08.219389Z3nodeID://b5446167942024-03-29T22:03:08.219389Z4nodeID://b5446186552024-03-29T22:03:08.219389Z2nodeID://b5446166632024-03-29T22:03:08.219389Z5nodeID://b5446168902024-03-29T22:03:08.219389Z4nodeID://b5446172532024-03-29T22:03:08.219389Z3nodeID://b5446185242024-03-29T22:03:08.219389Z2nodeID://b5446166472024-03-29T22:03:08.219389Z5nodeID://b5446179182024-03-29T22:03:08.219389Z2nodeID://b5446175992024-03-29T22:03:08.219389Z2nodeID://b5446185082024-03-29T22:03:08.219389Z2nodeID://b5446165162024-03-29T22:03:08.219389Z7nodeID://b5446186202024-03-29T22:03:08.219389Z2nodeID://b5446171062024-03-29T22:03:08.219389Z3nodeID://b5446180582024-03-29T22:03:08.219389Z2nodeID://b5446176952024-03-29T22:03:08.219389Z2nodeID://b5446166122024-03-29T22:03:08.219389Z6nodeID://b5446175642024-03-29T22:03:08.219389Z2nodeID://b5446172022024-03-29T22:03:08.219389Z3nodeID://b5446181542024-03-29T22:03:08.219389Z2nodeID://b5446169582024-03-29T22:03:08.219389Z4nodeID://b5446175482024-03-29T22:03:08.219389Z2nodeID://b5446188192024-03-29T22:03:08.219389Z2nodeID://b5446176602024-03-29T22:03:08.219389Z2nodeID://b5446189312024-03-29T22:03:08.219389Z2nodeID://b5446182502024-03-29T22:03:08.219389Z2nodeID://b5446174172024-03-29T22:03:08.219389Z3nodeID://b5446170982024-03-29T22:03:08.219389Z3nodeID://b5446183692024-03-29T22:03:08.219389Z2nodeID://b5446180072024-03-29T22:03:08.219389Z2nodeID://b5446189152024-03-29T22:03:08.219389Z2nodeID://b5446169232024-03-29T22:03:08.219389Z4nodeID://b5446185962024-03-29T22:03:08.219389Z2nodeID://b5446175132024-03-29T22:03:08.219389Z2nodeID://b5446171942024-03-29T22:03:08.219389Z3nodeID://b5446184652024-03-29T22:03:08.219389Z2nodeID://b5446169072024-03-29T22:03:08.219389Z4nodeID://b5446165882024-03-29T22:03:08.219389Z6nodeID://b5446170632024-03-29T22:03:08.219389Z3nodeID://b5446178592024-03-29T22:03:08.219389Z2nodeID://b5446179712024-03-29T22:03:08.219389Z2nodeID://b5446164572024-03-29T22:03:08.219389Z9nodeID://b5446172902024-03-29T22:03:08.219389Z3nodeID://b5446185612024-03-29T22:03:08.219389Z2nodeID://b287419142024-03-29T22:03:08.219389ZIn AML, a subset of cases evolve from a preceding clinically overt phase such as MDS or chronic myeloid leukemia (CML), characterized by clonal expansion of one or more blood lineages22,>>23<<. The founder mutations present in pre-leukemic cells are retained in the AML blasts, implicating them as putative initiating events and establishing clonal expansion as the first step in leukemogenesis. Interestingly, somatic mutations innodeID://b5446170472024-03-29T22:03:08.219389Z3nodeID://b5446183182024-03-29T22:03:08.219389Z2nodeID://b5446179552024-03-29T22:03:08.219389Z2nodeID://b5446165532024-03-29T22:03:08.219389Z7nodeID://b5446178242024-03-29T22:03:08.219389Z2nodeID://b5446184142024-03-29T22:03:08.219389Z2nodeID://b5446168992024-03-29T22:03:08.219389Z4nodeID://b5446180952024-03-29T22:03:08.219389Z2nodeID://b5446178082024-03-29T22:03:08.219389Z2nodeID://b5446170122024-03-29T22:03:08.219389Z3nodeID://b5446179202024-03-29T22:03:08.219389Z2nodeID://b5446164062024-03-29T22:03:08.219389Z12nodeID://b5446185102024-03-29T22:03:08.219389Z2nodeID://b5446188722024-03-29T22:03:08.219389Z2nodeID://b5446173582024-03-29T22:03:08.219389Z3nodeID://b5446169952024-03-29T22:03:08.219389Z3nodeID://b5446186292024-03-29T22:03:08.219389Z2nodeID://b5446188562024-03-29T22:03:08.219389Z2nodeID://b5446168642024-03-29T22:03:08.219389Z4nodeID://b5446180602024-03-29T22:03:08.219389Z2nodeID://b5446165022024-03-29T22:03:08.219389Z8nodeID://b5446174542024-03-29T22:03:08.219389Z3nodeID://b5446187252024-03-29T22:03:08.219389Z2nodeID://b5446168482024-03-29T22:03:08.219389Z4nodeID://b5446173232024-03-29T22:03:08.219389Z3nodeID://b5446169602024-03-29T22:03:08.219389Z4nodeID://b5446167172024-03-29T22:03:08.219389Z5nodeID://b5446175502024-03-29T22:03:08.219389Z2nodeID://b5446163982024-03-29T22:03:08.219389Z13nodeID://b5446188212024-03-29T22:03:08.219389Z2nodeID://b287419402024-03-29T22:03:08.219389ZPrior studies in T-ALL46 and B-ALL7,>>11<<,14 revealed the existence of genetically diverse subclones at diagnosis.nodeID://b5446176692024-03-29T22:03:08.219389Z2nodeID://b5446173072024-03-29T22:03:08.219389Z3nodeID://b5446182592024-03-29T22:03:08.219389Z2nodeID://b5446178962024-03-29T22:03:08.219389Z2nodeID://b5446183712024-03-29T22:03:08.219389Z2nodeID://b5446168132024-03-29T22:03:08.219389Z4nodeID://b5446164942024-03-29T22:03:08.219389Z8nodeID://b5446177652024-03-29T22:03:08.219389Z2nodeID://b5446183552024-03-29T22:03:08.219389Z2nodeID://b5446163632024-03-29T22:03:08.219389Z20nodeID://b5446182242024-03-29T22:03:08.219389Z2nodeID://b5446178612024-03-29T22:03:08.219389Z2nodeID://b5446163472024-03-29T22:03:08.219389Z38nodeID://b5446176182024-03-29T22:03:08.219389Z2nodeID://b5446172992024-03-29T22:03:08.219389Z3nodeID://b5446182082024-03-29T22:03:08.219389Z2nodeID://b5446183202024-03-29T22:03:08.219389Z2nodeID://b5446177142024-03-29T22:03:08.219389Z2nodeID://b5446173952024-03-29T22:03:08.219389Z3nodeID://b5446186662024-03-29T22:03:08.219389Z2nodeID://b5446172642024-03-29T22:03:08.219389Z3nodeID://b5446178102024-03-29T22:03:08.219389Z2nodeID://b5446166582024-03-29T22:03:08.219389Z5