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n2:pmcid
PMC0
bibo:doi
10.1038%2Fnature13038
n6:contains
_:vb28741918 _:vb28741901 _:vb28741946 _:vb28741930 _:vb28741933
Subject Item
_:vb28741901
rdf:type
n6:Section
dc:title
introduction
n6:contains
_:vb28741904 _:vb28741905 _:vb28741906 _:vb28741907 _:vb28741908 _:vb28741909 _:vb28741910 _:vb28741911 _:vb28741912 _:vb28741913 _:vb28741914 _:vb28741915 _:vb28741916 _:vb28741917 _:vb28741902 _:vb28741903
Subject Item
_:vb28741902
rdf:type
n2:Context
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There 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.
n2:mentions
n3:3614291 n3:2982210 n3:299069
Subject Item
_:vb28741903
rdf:type
n2:Context
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However 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 clone5,6.
n2:mentions
n3:24132290
Subject Item
_:vb28741904
rdf:type
n2:Context
rdf:value
However 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 at
n2:mentions
n3:22258609
Subject Item
_:vb28741905
rdf:type
n2:Context
rdf:value
However 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 at
n2:mentions
n3:23044827
Subject Item
_:vb28741906
rdf:type
n2:Context
rdf:value
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 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.
n2:mentions
n3:22645183 n3:21248843 n3:19812674 n3:20393555 n3:22237025 n3:20981101 n3:20981102 n3:21160474 n3:19039135
Subject Item
_:vb28741907
rdf:type
n2:Context
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Early 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.
n2:mentions
n3:19824828
Subject Item
_:vb28741908
rdf:type
n2:Context
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Early 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.
n2:mentions
n3:12379874
Subject Item
_:vb28741909
rdf:type
n2:Context
rdf:value
Early 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.
n2:mentions
n3:3940171
Subject Item
_:vb28741910
rdf:type
n2:Context
rdf:value
Early 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.
n2:mentions
n3:2841597
Subject Item
_:vb28741911
rdf:type
n2:Context
rdf:value
and 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 cell?
n2:mentions
n3:22417201
Subject Item
_:vb28741912
rdf:type
n2:Context
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these 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 lineages22,23.
n2:mentions
n3:22305562
Subject Item
_:vb28741913
rdf:type
n2:Context
rdf:value
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 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 mutations
n2:mentions
n3:23175121
Subject Item
_:vb28741914
rdf:type
n2:Context
rdf:value
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 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 in
n2:mentions
n3:22898539
Subject Item
_:vb28741915
rdf:type
n2:Context
rdf:value
Interestingly, 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 the
n2:mentions
n3:23001125
Subject Item
_:vb28741916
rdf:type
n2:Context
rdf:value
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 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 of
n2:mentions
n3:5237880
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_:vb28741917
rdf:type
n2:Context
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Recent 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. These
n2:mentions
n3:10861016
Subject Item
_:vb28741918
rdf:type
n6:Section
dc:title
results
n6:contains
_:vb28741919 _:vb28741928 _:vb28741929 _:vb28741924 _:vb28741925 _:vb28741926 _:vb28741927 _:vb28741920 _:vb28741921 _:vb28741922 _:vb28741923
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_:vb28741919
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Consistent with mutant allele frequencies reported in recent studies>>28<< DNMT3amut was found in 4 of 12 samples (mutant allele frequency ~50%) (Fig.
n2:mentions
n3:23634996
Subject Item
_:vb28741920
rdf:type
n2:Context
rdf:value
Consistent with published data>>29<<–31, 17 of 71 AML samples (24%) carried mutations in DNMT3a, and 15 of these 17 (88%) also carried NPM1c.
n2:mentions
n3:22417203 n3:21067377 n3:21399634
Subject Item
_:vb28741921
rdf:type
n2:Context
rdf:value
DNMT3amut 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.
n2:mentions
n3:22645183
Subject Item
_:vb28741922
rdf:type
n2:Context
rdf:value
DNMT3amut 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.
n2:mentions
n3:23634996
Subject Item
_:vb28741923
rdf:type
n2:Context
rdf:value
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.
n2:mentions
n3:23704090
Subject Item
_:vb28741924
rdf:type
n2:Context
rdf:value
A 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), granulocyte
n2:mentions
n3:20543838 n3:21737740 n3:23708252
Subject Item
_:vb28741925
rdf:type
n2:Context
rdf:value
Although 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 allele
n2:mentions
n3:10891424
Subject Item
_:vb28741926
rdf:type
n2:Context
rdf:value
Collectively, 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.
n2:mentions
n3:2982210
Subject Item
_:vb28741927
rdf:type
n2:Context
rdf:value
Collectively, 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<<.
n2:mentions
n3:2009365
Subject Item
_:vb28741928
rdf:type
n2:Context
rdf:value
Only 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 NPM1c
n2:mentions
n3:21873988
Subject Item
_:vb28741929
rdf:type
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rdf:value
3a 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-HSC
n2:mentions
n3:21873988
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_:vb28741930
rdf:type
n6:Section
dc:title
methods
n6:contains
_:vb28741932 _:vb28741931
Subject Item
_:vb28741931
rdf:type
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rdf:value
For limiting dilution assays, the frequency of repopulating cells was calculated using ELDA software>>49<<.
n2:mentions
n3:19567251
Subject Item
_:vb28741932
rdf:type
n2:Context
rdf:value
html, provided by the Walter and Eliza Hall Institute)>>49<<. P-values were derived using two-tailed Student’s t-tests.
n2:mentions
n3:19567251
Subject Item
_:vb28741933
rdf:type
n6:Section
dc:title
discussion
n6:contains
_:vb28741936 _:vb28741937 _:vb28741938 _:vb28741939 _:vb28741940 _:vb28741941 _:vb28741942 _:vb28741943 _:vb28741944 _:vb28741945 _:vb28741934 _:vb28741935
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_:vb28741934
rdf:type
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Pre-leukemic progenitors of varying phenotypes have been reported in other types of hematologic malignancies>>25<<,39–41, although functional studies were limited.
n2:mentions
n3:5237880
Subject Item
_:vb28741935
rdf:type
n2:Context
rdf:value
Pre-leukemic progenitors of varying phenotypes have been reported in other types of hematologic malignancies25,>>39<<–41, although functional studies were limited.
n2:mentions
n3:21840488 n3:21828135 n3:21415852
Subject Item
_:vb28741936
rdf:type
n2:Context
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Our 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-leukemic
n2:mentions
n3:10861016
Subject Item
_:vb28741937
rdf:type
n2:Context
rdf:value
Our 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.
n2:mentions
n3:17420264
Subject Item
_:vb28741938
rdf:type
n2:Context
rdf:value
Prior studies in T-ALL>>46<< and B-ALL7,11,14 revealed the existence of genetically diverse subclones at diagnosis.
n2:mentions
n3:21464223
Subject Item
_:vb28741939
rdf:type
n2:Context
rdf:value
Prior studies in T-ALL46 and B-ALL>>7<<,11,14 revealed the existence of genetically diverse subclones at diagnosis.
n2:mentions
n3:21160474
Subject Item
_:vb28741940
rdf:type
n2:Context
rdf:value
Prior studies in T-ALL46 and B-ALL7,>>11<<,14 revealed the existence of genetically diverse subclones at diagnosis.
n2:mentions
n3:21248843
Subject Item
_:vb28741941
rdf:type
n2:Context
rdf:value
Prior studies in T-ALL46 and B-ALL7,11,>>14<< revealed the existence of genetically diverse subclones at diagnosis.
n2:mentions
n3:19039135
Subject Item
_:vb28741942
rdf:type
n2:Context
rdf:value
Prior 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 that
n2:mentions
n3:23523389
Subject Item
_:vb28741943
rdf:type
n2:Context
rdf:value
As 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 which
n2:mentions
n3:22237025
Subject Item
_:vb28741944
rdf:type
n2:Context
rdf:value
As 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 which
n2:mentions
n3:22645183
Subject Item
_:vb28741945
rdf:type
n2:Context
rdf:value
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 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.
n2:mentions
n3:23523389
Subject Item
_:vb28741946
rdf:type
n6:Section
dc:title
extended data
n6:contains
_:vb28741948 _:vb28741949 _:vb28741947
Subject Item
_:vb28741947
rdf:type
n2:Context
rdf:value
PCR analysis of FLT3-ITD>>50<< in stem/progenitor, mature lymphoid and blast (CD45dim CD33+) cell populations from patient no.
n2:mentions
n3:12239147
Subject Item
_:vb28741948
rdf:type
n2:Context
rdf:value
Departures 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.
n2:mentions
n3:22127862
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_:vb28741949
rdf:type
n2:Context
rdf:value
Shown 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<<.
n2:mentions
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