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PMC0
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10.1186%2F1756-8722-2-23
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introduction
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The overall 5-year survival rate for AML is still less than 50% in adults and significantly lower in the elderly [>>1<<]. The median survival in patients over the age of 65 is less than one year and only 20% of these patients survive two years [2]. Treatment for all subtypes of AML, except the M3 subtype, involves combination chemotherapy and a possible
n2:mentions
n3:15155136
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_:vb5369311
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The median survival in patients over the age of 65 is less than one year and only 20% of these patients survive two years [>>2<<]. Treatment for all subtypes of AML, except the M3 subtype, involves combination chemotherapy and a possible hematopoietic stem cell transplant as part of consolidation therapy. Acute Promyelocytic Leukemia (APL, M3 subtype) is treated
n2:mentions
n3:16616042
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Acute Promyelocytic Leukemia (APL, M3 subtype) is treated with a combination of the differentiation-inducing agent all-trans retinoic acid and chemotherapy resulting in the presumed cure of 75–85% of patients [>>3<<]. In general, the prognosis of patients with AML is currently based upon the presence or absence of cytogenetic abnormalities and is divided into favorable, intermediate and unfavorable subgroups (see table 1) [4]. There is heterogeneity
n2:mentions
n3:15124685
Subject Item
_:vb5369313
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In general, the prognosis of patients with AML is currently based upon the presence or absence of cytogenetic abnormalities and is divided into favorable, intermediate and unfavorable subgroups (see table 1) [>>4<<]. There is heterogeneity within these subgroups, especially the intermediate subgroup, and the age of the patient is also an important prognostic factor. One study estimated the 5 year overall survival (OS) of the favorable subgroup at
n2:mentions
n3:9045301
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_:vb5369314
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One study estimated the 5 year overall survival (OS) of the favorable subgroup at 55%, the intermediate subgroup at 38% and the unfavorable subgroup at 11% [>>5<<]. Patients who have the following cytogenetic abnormalities: inv(16), t(15;17) (the translocation found in APL), or t(8;21) have a favorable prognosis while patients with several other cytogenetic abnormalities including monosomy 5,
n2:mentions
n3:11110676
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Mutations of NPM1 have recently been described as one of the most frequent genetic lesions in AML, occurring in 50–60% of adult AML with normal karyotype [>>6<<,7]. Additional evaluation has shown that mutations in NPM1 are rare in other risk groups of AML and in one study, no NPM1 mutations were shown in patients with favorable cytogenetics [7].
n2:mentions
n3:16109776
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Mutations of NPM1 have recently been described as one of the most frequent genetic lesions in AML, occurring in 50–60% of adult AML with normal karyotype [6,>>7<<]. Additional evaluation has shown that mutations in NPM1 are rare in other risk groups of AML and in one study, no NPM1 mutations were shown in patients with favorable cytogenetics [7].
n2:mentions
n3:17076533
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Additional evaluation has shown that mutations in NPM1 are rare in other risk groups of AML and in one study, no NPM1 mutations were shown in patients with favorable cytogenetics [>>7<<]. The NPM1 gene encodes a nucleo-cytoplasmic shuttling protein that regulates the ARF-p53 tumor-supressor pathway [8,9]. Mutations in this gene result in an abnormal accumulation of the NPM1 protein in cytoplasm. Two types of mutations
n2:mentions
n3:17076533
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_:vb5369318
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The NPM1 gene encodes a nucleo-cytoplasmic shuttling protein that regulates the ARF-p53 tumor-supressor pathway [>>8<<,9]. Mutations in this gene result in an abnormal accumulation of the NPM1 protein in cytoplasm. Two types of mutations have been described to date. The first and most frequent mutations consists of a 4-nucleotide (nt) insertion (YWTG;
n2:mentions
n3:15659725
Subject Item
_:vb5369319
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The NPM1 gene encodes a nucleo-cytoplasmic shuttling protein that regulates the ARF-p53 tumor-supressor pathway [8,>>9<<]. Mutations in this gene result in an abnormal accumulation of the NPM1 protein in cytoplasm. Two types of mutations have been described to date. The first and most frequent mutations consists of a 4-nucleotide (nt) insertion (YWTG; YUPAC
n2:mentions
n3:17008539
Subject Item
_:vb5369320
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In all mutated cases, the resulting frameshift led to a product five amino acids longer with the new C-terminal tail CFSQVSLRK, peculiar to the NPM1-mutated product [>>7<<].
n2:mentions
n3:17076533
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Therefore, the loss of NPM1 expression can contribute to tumorgenesis [>>10<<]. Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies [7,11-13].
n2:mentions
n3:16794633
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_:vb5369322
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Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies [>>7<<,11-13].
n2:mentions
n3:17076533
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_:vb5369323
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Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies [7,>>11<<-13].
n2:mentions
n3:12031912 n3:15973451 n3:16541144
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NPM1 gene mutations appear to occur more frequently in adult female AML patients [>>14<<-16] and also tend to be associated with:
n2:mentions
n3:16076867 n3:16051734 n3:16455956
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NPM1 gene mutations appear to occur more frequently in adult female AML patients [14-16] and also tend to be associated with: a) higher white blood cell count, b) monocytic differentiation (in particular FAB M5b AML subtype) [>>17<<], c) wide morphologic spectrum, d) multilineage involvement [9], e) lack of CD34/CD34-negativity [7,9,11], f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18]
n2:mentions
n3:16046528
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in adult female AML patients [14-16] and also tend to be associated with: a) higher white blood cell count, b) monocytic differentiation (in particular FAB M5b AML subtype) [17], c) wide morphologic spectrum, d) multilineage involvement [>>9<<], e) lack of CD34/CD34-negativity [7,9,11], f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in
n2:mentions
n3:17008539
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and also tend to be associated with: a) higher white blood cell count, b) monocytic differentiation (in particular FAB M5b AML subtype) [17], c) wide morphologic spectrum, d) multilineage involvement [9], e) lack of CD34/CD34-negativity [>>7<<,9,11], f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation
n2:mentions
n3:17076533
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also tend to be associated with: a) higher white blood cell count, b) monocytic differentiation (in particular FAB M5b AML subtype) [17], c) wide morphologic spectrum, d) multilineage involvement [9], e) lack of CD34/CD34-negativity [7,>>9<<,11], f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation
n2:mentions
n3:17008539
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tend to be associated with: a) higher white blood cell count, b) monocytic differentiation (in particular FAB M5b AML subtype) [17], c) wide morphologic spectrum, d) multilineage involvement [9], e) lack of CD34/CD34-negativity [7,9,>>11<<], f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation
n2:mentions
n3:12031912
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a) higher white blood cell count, b) monocytic differentiation (in particular FAB M5b AML subtype) [17], c) wide morphologic spectrum, d) multilineage involvement [9], e) lack of CD34/CD34-negativity [7,9,11], f) normal cytogenetics [>>18<<], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation [7,15].
n2:mentions
n3:15994285
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(in particular FAB M5b AML subtype) [17], c) wide morphologic spectrum, d) multilineage involvement [9], e) lack of CD34/CD34-negativity [7,9,11], f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [>>17<<], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation [7,15].
n2:mentions
n3:16046528
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[17], c) wide morphologic spectrum, d) multilineage involvement [9], e) lack of CD34/CD34-negativity [7,9,11], f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [>>18<<] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation [7,15].
n2:mentions
n3:15994285
Subject Item
_:vb5369333
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f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation [>>7<<,15]. Patients with only an NPM1 mutation exhibit higher complete remission (CR) and significantly better OS [14-16], event free survival (EFS) [15], and disease free survival (DFS) as well as a lower cumulative incidence of relapse [6,16].
n2:mentions
n3:17076533
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_:vb5369334
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f) normal cytogenetics [18], g) a decreased prevalence of CEBPα mutations [17], h) high frequency of FLT3-ITD gene mutation [18] and i) a trend toward favorable clinical outcome, especially in patients without a FLT3 gene mutation [7,>>15<<]. Patients with only an NPM1 mutation exhibit higher complete remission (CR) and significantly better OS [14-16], event free survival (EFS) [15], and disease free survival (DFS) as well as a lower cumulative incidence of relapse [6,16].
n2:mentions
n3:16076867
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Patients with only an NPM1 mutation exhibit higher complete remission (CR) and significantly better OS [>>14<<-16], event free survival (EFS) [15], and disease free survival (DFS) as well as a lower cumulative incidence of relapse [6,16].
n2:mentions
n3:16051734 n3:16076867 n3:16455956
Subject Item
_:vb5369336
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Patients with only an NPM1 mutation exhibit higher complete remission (CR) and significantly better OS [14-16], event free survival (EFS) [>>15<<], and disease free survival (DFS) as well as a lower cumulative incidence of relapse [6,16].
n2:mentions
n3:16076867
Subject Item
_:vb5369337
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Patients with only an NPM1 mutation exhibit higher complete remission (CR) and significantly better OS [14-16], event free survival (EFS) [15], and disease free survival (DFS) as well as a lower cumulative incidence of relapse [>>6<<,16]. The various study outcomes of risk associated with NPM1 status are summarized in Table 2.
n2:mentions
n3:16109776
Subject Item
_:vb5369338
rdf:type
n2:Context
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Patients with only an NPM1 mutation exhibit higher complete remission (CR) and significantly better OS [14-16], event free survival (EFS) [15], and disease free survival (DFS) as well as a lower cumulative incidence of relapse [6,>>16<<]. The various study outcomes of risk associated with NPM1 status are summarized in Table 2.
n2:mentions
n3:16455956
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StudyNumber of NPM1 mutants/total cases studiedTreatmentDemographics of those patients with NMP1 mutations+ NPM1 mutant assessment of riskVerhaak, et al [>>6<<]95/275(34.5%)Dutch Belgian Hematology Oncology Cooperative Groop (HOVON) protocols- Median age 47 yo- 60% of those with FLT3 ITD- decreased in those age < 35 yo- 42% of those with WBC >20 KHREFS 1.96DFS 2.0OS 2.13Döhner, et al
n2:mentions
n3:16109776
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_:vb5369340
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et al [6]95/275(34.5%)Dutch Belgian Hematology Oncology Cooperative Groop (HOVON) protocols- Median age 47 yo- 60% of those with FLT3 ITD- decreased in those age < 35 yo- 42% of those with WBC >20 KHREFS 1.96DFS 2.0OS 2.13Döhner, et al [>>14<<]145/300(48.3%)AML Study Group (AMLSG)AML HD93AML HD98-A- Increased in M4/M5- extramedullary LAD- Female predominance- Decreased CD34 antigen expression- Increased LDH- Associated with FLT3 ITD- WBC >20 K- Increased bone marrow blast
n2:mentions
n3:16051734
Subject Item
_:vb5369341
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in M4/M5- extramedullary LAD- Female predominance- Decreased CD34 antigen expression- Increased LDH- Associated with FLT3 ITD- WBC >20 K- Increased bone marrow blast countsOdds ratio (OR) after inductionCR 2.81Schnittger, et al [>>15<<]212/401(52.9%)German AMLCG99 study- Associated with FLT3 ITD- Without FLT3, OS and EFS increased- Female predominanceRelative risk (RR)EFS 0.527Theide, et al [16]408/1485(27.5%)Deutsche Studieninitiative Leukämie (DSIL) AML 96 protocol-
n2:mentions
n3:16076867
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_:vb5369342
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blast countsOdds ratio (OR) after inductionCR 2.81Schnittger, et al [15]212/401(52.9%)German AMLCG99 study- Associated with FLT3 ITD- Without FLT3, OS and EFS increased- Female predominanceRelative risk (RR)EFS 0.527Theide, et al [>>16<<]408/1485(27.5%)Deutsche Studieninitiative Leukämie (DSIL) AML 96 protocol- High bone marrow blasts- Female predominance- WBC >20 K- Association with FLT3-ITD mutationsOROS 0.76DFS 0.66Boissel, et al [17]50/106(47%)French Leukemia French
n2:mentions
n3:16455956
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_:vb5369343
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risk (RR)EFS 0.527Theide, et al [16]408/1485(27.5%)Deutsche Studieninitiative Leukämie (DSIL) AML 96 protocol- High bone marrow blasts- Female predominance- WBC >20 K- Association with FLT3-ITD mutationsOROS 0.76DFS 0.66Boissel, et al [>>17<<]50/106(47%)French Leukemia French Association (ALFA)ALFA90ALFA9802- Increased in FAB M4/M5- 25% with FLT3-ITD- Decreased CEBPA- WBC >20 KNo difference in CR or long term outcomesSuzuki, et al [18]64/257(24.9%)Japan Adult Leukemia Study
n2:mentions
n3:16046528
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_:vb5369344
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0.76DFS 0.66Boissel, et al [17]50/106(47%)French Leukemia French Association (ALFA)ALFA90ALFA9802- Increased in FAB M4/M5- 25% with FLT3-ITD- Decreased CEBPA- WBC >20 KNo difference in CR or long term outcomesSuzuki, et al [>>18<<]64/257(24.9%)Japan Adult Leukemia Study Group protocols- Associated with FLT3-ITD- NPM1 mutant unfavorable factor for relapseOR 2.106- NPM1 wild type unfavorable for CROR 4.908-NPM1 mutant with FLT3-ITD favorable for CROR
n2:mentions
n3:15994285
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Detection of NPM1 gene mutations may be useful in the dissection of the heterogeneous group of AML patients with normal karyotype into prognostically different subgroups [>>7<<]. Further, due to their frequency and stability, NPM1 mutations may become a new tool for monitoring minimal residual disease in AML-patients with a normal karyotype [9].
n2:mentions
n3:17076533
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_:vb5369346
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Further, due to their frequency and stability, NPM1 mutations may become a new tool for monitoring minimal residual disease in AML-patients with a normal karyotype [>>9<<].
n2:mentions
n3:17008539
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_:vb5369347
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FLT3 is the most commonly mutated gene in AML with the mutation occurring in approximately 30–40% of AML patients [>>19<<]. The most common mutation consists of an internal tandem duplication (FLT3-ITD) in the juxtamembrane domain of the FLT3 gene. FLT3-ITD results in a constitutively active FLT3 protein that promotes Stat 5 phosphorylation. The net
n2:mentions
n3:16757428
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_:vb5369348
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The net consequence of FLT3/Stat5 constitutive activation is uncontrolled hematopoietic cell proliferation [>>20<<]. AML patients who carry the FLT3-ITD mutation appear to have poorer clinical outcomes. Adult patients usually have a higher prevalence of FLT3-ITD than pediatric AML patients. This observation may partially explain why adult AML has a
n2:mentions
n3:16263569
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_:vb5369349
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Clinically, AML patients with FLT3-ITD tend to have higher WBC counts and an increase percentage of leukemic blasts [>>21<<]. A missense mutation in the activation loop (FLT3-ALM) of the second tyrosine kinase domain of FLT3 at Asp835 leads to another common FLT3 mutant (FLT3-TKD) that is found in approximately 5–10% of AML patients [22]. Although the clinical
n2:mentions
n3:12393388
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_:vb5369350
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rdf:value
A missense mutation in the activation loop (FLT3-ALM) of the second tyrosine kinase domain of FLT3 at Asp835 leads to another common FLT3 mutant (FLT3-TKD) that is found in approximately 5–10% of AML patients [>>22<<]. Although the clinical significance of this FLT3 mutation especially in NC-AML is not yet clear, several studies indicate that it is also an adverse prognostic indicator [19,21]. The associated risk of FLT3 status determined by these
n2:mentions
n3:11290608
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_:vb5369351
rdf:type
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rdf:value
Although the clinical significance of this FLT3 mutation especially in NC-AML is not yet clear, several studies indicate that it is also an adverse prognostic indicator [>>19<<,21]. The associated risk of FLT3 status determined by these studies are summarized in Table 3.
n2:mentions
n3:16757428
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_:vb5369352
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Although the clinical significance of this FLT3 mutation especially in NC-AML is not yet clear, several studies indicate that it is also an adverse prognostic indicator [19,>>21<<]. The associated risk of FLT3 status determined by these studies are summarized in Table 3.
n2:mentions
n3:12393388
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_:vb5369353
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StudyNumber of FLT3 mutants/total cases studiedTreatmentDemographics of those patients with FLT3-ITD+ FLT3-ITD assessment of riskFröhling, et al [>>21<<]119/523 all comers(22.8%)71/224 NC AML(32%)AML Study Group (AMLSG)AML HD93AML HD98-A- Associated with high WBC- Associated with de novo AML- Increased bone marrow and peripheral blood blasts- Increased LDHHazard ratio (HR)Remission
n2:mentions
n3:12393388
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_:vb5369354
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NC AML(32%)AML Study Group (AMLSG)AML HD93AML HD98-A- Associated with high WBC- Associated with de novo AML- Increased bone marrow and peripheral blood blasts- Increased LDHHazard ratio (HR)Remission duration2.35Kainz, et al[>>23<<]26/100(26%)16/53 NC AML(30%)Various protocols- Increased in M4 (50%)- Increased LDH- WBC >10 KORCR 0.31Relapse rate 8.3OS 0.17Ciolli, et al[24]25/100(25%)Various protocols- WBC > 30 K- Decreased incidence of secondary AML- Female
n2:mentions
n3:12522450
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_:vb5369355
rdf:type
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rdf:value
and peripheral blood blasts- Increased LDHHazard ratio (HR)Remission duration2.35Kainz, et al[23]26/100(26%)16/53 NC AML(30%)Various protocols- Increased in M4 (50%)- Increased LDH- WBC >10 KORCR 0.31Relapse rate 8.3OS 0.17Ciolli, et al[>>24<<]25/100(25%)Various protocols- WBC > 30 K- Decreased incidence of secondary AML- Female predominance- Increased LDHHRRFS 3.1Post remission survival 2.1Stirewelt, et al [26]48/151(31.8%)Southwest Oncology GroupSWOG 9333SWOG 9500- High bone
n2:mentions
n3:15061200
Subject Item
_:vb5369356
rdf:type
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rdf:value
LDH- WBC >10 KORCR 0.31Relapse rate 8.3OS 0.17Ciolli, et al[24]25/100(25%)Various protocols- WBC > 30 K- Decreased incidence of secondary AML- Female predominance- Increased LDHHRRFS 3.1Post remission survival 2.1Stirewelt, et al [>>26<<]48/151(31.8%)Southwest Oncology GroupSWOG 9333SWOG 9500- High bone marrow blasts- High peripheral blood blasts- WBC >30 KHROS 1.35RFS 1.7Whitman, et al [27]23/82(28%)CALGB protocol- All patients evaluated had NC AML, age <60, and de novo
n2:mentions
n3:16368883
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_:vb5369357
rdf:type
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rdf:value
predominance- Increased LDHHRRFS 3.1Post remission survival 2.1Stirewelt, et al [26]48/151(31.8%)Southwest Oncology GroupSWOG 9333SWOG 9500- High bone marrow blasts- High peripheral blood blasts- WBC >30 KHROS 1.35RFS 1.7Whitman, et al [>>27<<]23/82(28%)CALGB protocol- All patients evaluated had NC AML, age <60, and de novo AML- Median age 37 yo- N = 8 FLT3ITD/-No clear evidence in difference between groups, but trend towards decreased OS with FLT3ITD/-Thiede, et al
n2:mentions
n3:11585760
Subject Item
_:vb5369358
rdf:type
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rdf:value
al [27]23/82(28%)CALGB protocol- All patients evaluated had NC AML, age <60, and de novo AML- Median age 37 yo- N = 8 FLT3ITD/-No clear evidence in difference between groups, but trend towards decreased OS with FLT3ITD/-Thiede, et al [>>28<<]200/979(20.4%)Various protocols- Increased in M5- WBC >50 K- Increased bone marrow blastsORMut/wt ratio 1- all agesOS 1.8DFS 3.2- age < 60DFS 4.2Mut/wt ratio 2- all agesOS 2.8DFS 8- age <
n2:mentions
n3:12036858
Subject Item
_:vb5369359
rdf:type
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Several studies have demonstrated that FLT3-ITD in NC-AML patients correlates with an adverse prognosis for both DFS and OS [>>23<<-25]. Not only does the presence of FLT3-ITD impart a poor prognosis, but the size of the internal tandem duplication is significant. The duplication can range in size from three to hundreds of nucleotides and longer duplications correlate
n2:mentions
n3:15746041 n3:15061200 n3:12522450
Subject Item
_:vb5369360
rdf:type
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rdf:value
The duplication can range in size from three to hundreds of nucleotides and longer duplications correlate with a worse OS [>>26<<]. In addition to the mutant allele, the status of the wild-type allele in patients with FLT3-ITD has been demonstrated to have prognostic significance. Patients who lack the wild-type allele have a worse prognosis [27]. In those who
n2:mentions
n3:16368883
Subject Item
_:vb5369361
rdf:type
n2:Context
rdf:value
Patients who lack the wild-type allele have a worse prognosis [>>27<<]. In those who express the wild-type allele, the ratio of the mutant to wild-type level of FLT3-ITD has a strong correlation to survival.
n2:mentions
n3:11585760
Subject Item
_:vb5369362
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The DFS and OS for patients with a lower ratio were no different than the group of patients without FLT3 abnormalities [>>28<<].
n2:mentions
n3:12036858
Subject Item
_:vb5369363
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Over-expression of FLT3 even in the absence of FLT3-ITD is also an unfavorable prognostic factor for OS [>>29<<]. As FLT3-ITD is an adverse prognostic factor, it has been speculated that patients with this genetic abnormality should be considered for more intensive therapy. However, a large study of 1135 adult patients with AML including 25% with
n2:mentions
n3:14604973
Subject Item
_:vb5369364
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However, this study did not illustrate significant correlations with outcomes and FLT3 mutational status [>>31<<].
n2:mentions
n3:18977345
Subject Item
_:vb5369365
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Nevertheless, there is optimism that FLT3 inhibitors may be more efficacious when used in combination therapies [>>32<<]. Besides being a useful as a prognostic marker and a therapeutic target, FLT3-ITD has also been used for minimal residual disease monitoring [33].
n2:mentions
n3:15604885
Subject Item
_:vb5369366
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Besides being a useful as a prognostic marker and a therapeutic target, FLT3-ITD has also been used for minimal residual disease monitoring [>>33<<].
n2:mentions
n3:15921740
Subject Item
_:vb5369367
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Overrepresented chromosomal material from 8q, 11q23, 21q, and 22q was found recurrently and in several cases this was due to the amplification of the MLL (located at 11q23) and AML1/RUNX1 (located at 22q22) genes [>>34<<]. MLL encodes a histone methyltransferase that plays a role in hematopoiesis by regulating homeobox genes. In mice heterozygous for MLL, both hematopoietic abnormalities are found as well as decreased Hox gene expression [35].
n2:mentions
n3:11979548
Subject Item
_:vb5369368
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In mice heterozygous for MLL, both hematopoietic abnormalities are found as well as decreased Hox gene expression [>>35<<].
n2:mentions
n3:7477409
Subject Item
_:vb5369369
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Interestingly, the silencing of wild-type MLL in blasts positive for MLL-PTD was reversed by DNA methyltransferase and histone deacetylase inhibitors [>>36<<]. These findings indicate the potential therapeutic role of the DNA methyltransferase and histone deacetylase inhibitors such as decitabine and valpoic acid in these AML patients.
n2:mentions
n3:15774615
Subject Item
_:vb5369370
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In this study, MLL-PTD was an adverse prognostic indicator as the median remission duration was 19 months in the absence of MLL-PTD and 7.75 months in its presence [>>37<<]. In general, the majority of studies indicate that MLL-PTD is poor prognostic indicator in NC-AML including median survival and relapse-free interval [38]. Additionally, the use of MLL-PTD for minimal residual disease monitoring has been
n2:mentions
n3:12149299
Subject Item
_:vb5369371
rdf:type
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In general, the majority of studies indicate that MLL-PTD is poor prognostic indicator in NC-AML including median survival and relapse-free interval [>>38<<]. Additionally, the use of MLL-PTD for minimal residual disease monitoring has been shown to be effective in detecting relapse prior to clinical manifestations [39].
n2:mentions
n3:10803509
Subject Item
_:vb5369372
rdf:type
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Additionally, the use of MLL-PTD for minimal residual disease monitoring has been shown to be effective in detecting relapse prior to clinical manifestations [>>39<<].
n2:mentions
n3:15996925
Subject Item
_:vb5369373
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CEBPα is an essential transcription factor for granulocytic differentiation as demonstrated by CEBPα-null mice that lack mature granulocytes [>>40<<,41]. Studies have reported N- and C-terminal CEBPα mutations in approximately 15% to 20% of AML [42].
n2:mentions
n3:11242107
Subject Item
_:vb5369374
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CEBPα is an essential transcription factor for granulocytic differentiation as demonstrated by CEBPα-null mice that lack mature granulocytes [40,>>41<<]. Studies have reported N- and C-terminal CEBPα mutations in approximately 15% to 20% of AML [42].
n2:mentions
n3:12692518
Subject Item
_:vb5369375
rdf:type
n2:Context
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Studies have reported N- and C-terminal CEBPα mutations in approximately 15% to 20% of AML [>>42<<]. The mutant proteins act in a dominant-negative manner to block DNA binding and transactivation of granulocyte target genes resulting in the failure of granulocytic differentiation [40]. Patients with a CEBPα mutation have higher
n2:mentions
n3:14726504
Subject Item
_:vb5369376
rdf:type
n2:Context
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The mutant proteins act in a dominant-negative manner to block DNA binding and transactivation of granulocyte target genes resulting in the failure of granulocytic differentiation [>>40<<]. Patients with a CEBPα mutation have higher hemoglobin levels, lower platelet counts, higher blast counts, and are less likely to present with lymphadenopathy or extramedullary leukemia compared to patients without a CEBPα mutation.
n2:mentions
n3:11242107
Subject Item
_:vb5369377
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Suprisingly, as CEBPα is required for differentiation, mutation of CEBPα is correlated with beneficial effects on remission, CR duration [>>42<<], event-free survival [17], DFS [25], and OS [41].
n2:mentions
n3:14726504
Subject Item
_:vb5369378
rdf:type
n2:Context
rdf:value
Suprisingly, as CEBPα is required for differentiation, mutation of CEBPα is correlated with beneficial effects on remission, CR duration [42], event-free survival [>>17<<], DFS [25], and OS [41].
n2:mentions
n3:16046528
Subject Item
_:vb5369379
rdf:type
n2:Context
rdf:value
Suprisingly, as CEBPα is required for differentiation, mutation of CEBPα is correlated with beneficial effects on remission, CR duration [42], event-free survival [17], DFS [>>25<<], and OS [41]. While there is no significant difference in CR rates between patients with and without CEBPα mutations [25,42], mutations are associated with a significantly reduced hazard ratio for death and event free survival [41].
n2:mentions
n3:15746041
Subject Item
_:vb5369380
rdf:type
n2:Context
rdf:value
Suprisingly, as CEBPα is required for differentiation, mutation of CEBPα is correlated with beneficial effects on remission, CR duration [42], event-free survival [17], DFS [25], and OS [>>41<<]. While there is no significant difference in CR rates between patients with and without CEBPα mutations [25,42], mutations are associated with a significantly reduced hazard ratio for death and event free survival [41].
n2:mentions
n3:12692518
Subject Item
_:vb5369381
rdf:type
n2:Context
rdf:value
While there is no significant difference in CR rates between patients with and without CEBPα mutations [>>25<<,42], mutations are associated with a significantly reduced hazard ratio for death and event free survival [41].
n2:mentions
n3:15746041
Subject Item
_:vb5369382
rdf:type
n2:Context
rdf:value
While there is no significant difference in CR rates between patients with and without CEBPα mutations [25,>>42<<], mutations are associated with a significantly reduced hazard ratio for death and event free survival [41].
n2:mentions
n3:14726504
Subject Item
_:vb5369383
rdf:type
n2:Context
rdf:value
While there is no significant difference in CR rates between patients with and without CEBPα mutations [25,42], mutations are associated with a significantly reduced hazard ratio for death and event free survival [>>41<<]. CEBPα mutations appear to be an independent prognostic factor even in the presence of FLT3 and MLL mutations. Studies have shown that there is no significant overlap between the patients with CEBPα mutation and patients with FLT3-ITD or
n2:mentions
n3:12692518
Subject Item
_:vb5369384
rdf:type
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rdf:value
Studies have shown that there is no significant overlap between the patients with CEBPα mutation and patients with FLT3-ITD or MLL-PTD mutations, suggesting that CEBPα mutations define a distinct biologic subclass of NC-AML [>>42<<]. CEBPα mutation is an independent prognostic marker for OS irrespective of age, MLL-PTD, and FLT3-ITD status [43] and is another marker that permits the division of NC-AML into distinct clinical groups [25].
n2:mentions
n3:14726504
Subject Item
_:vb5369385
rdf:type
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CEBPα mutation is an independent prognostic marker for OS irrespective of age, MLL-PTD, and FLT3-ITD status [>>43<<] and is another marker that permits the division of NC-AML into distinct clinical groups [25].
n2:mentions
n3:12351377
Subject Item
_:vb5369386
rdf:type
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rdf:value
CEBPα mutation is an independent prognostic marker for OS irrespective of age, MLL-PTD, and FLT3-ITD status [43] and is another marker that permits the division of NC-AML into distinct clinical groups [>>25<<].
n2:mentions
n3:15746041
Subject Item
_:vb5369387
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rdf:value
BAALC has been postulated to function in the cytoskeleton network due to its cellular location [>>44<<,45]. Several studies have demonstrated that high BAALC expression is a poor prognostic indicator in NC-AML for such factors as OS, DFS, and resistant disease [46,47]. In one study of 86 AML patients with NC-AML, high expression of BAALC
n2:mentions
n3:11707601
Subject Item
_:vb5369388
rdf:type
n2:Context
rdf:value
BAALC has been postulated to function in the cytoskeleton network due to its cellular location [44,>>45<<]. Several studies have demonstrated that high BAALC expression is a poor prognostic indicator in NC-AML for such factors as OS, DFS, and resistant disease [46,47]. In one study of 86 AML patients with NC-AML, high expression of BAALC was
n2:mentions
n3:14585369
Subject Item
_:vb5369389
rdf:type
n2:Context
rdf:value
Several studies have demonstrated that high BAALC expression is a poor prognostic indicator in NC-AML for such factors as OS, DFS, and resistant disease [>>46<<,47]. In one study of 86 AML patients with NC-AML, high expression of BAALC was found to be an independent risk factor for both inferior OS (1.7 vs. 5.8 years) and DFS (1.4 vs 7.3 years). Different post-remission strategies among patients
n2:mentions
n3:12750167
Subject Item
_:vb5369390
rdf:type
n2:Context
rdf:value
Several studies have demonstrated that high BAALC expression is a poor prognostic indicator in NC-AML for such factors as OS, DFS, and resistant disease [46,>>47<<]. In one study of 86 AML patients with NC-AML, high expression of BAALC was found to be an independent risk factor for both inferior OS (1.7 vs. 5.8 years) and DFS (1.4 vs 7.3 years). Different post-remission strategies among patients
n2:mentions
n3:16418499
Subject Item
_:vb5369391
rdf:type
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rdf:value
However, high BAALC expressive patients who underwent allogeneic stem cell transplantation have lower cumulative relapse rate compared to those who underwent autologous stem cell transplantation [>>47<<].
n2:mentions
n3:16418499
Subject Item
_:vb5369392
rdf:type
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rdf:value
In AML it has been found as part of the translocation t(12;22)(p13;q11) which leads to the MN1-TEL fusion gene [>>48<<]. In animal models, the MN1-TEL fusion gene collaborates with HOXA9 to induce AML [49]. Recently, high levels of expression of MN1 have been found to be a prognostic marker in NC-AML. Though the exact function of MN1 in hematopoietic
n2:mentions
n3:12569362
Subject Item
_:vb5369393
rdf:type
n2:Context
rdf:value
In animal models, the MN1-TEL fusion gene collaborates with HOXA9 to induce AML [>>49<<]. Recently, high levels of expression of MN1 have been found to be a prognostic marker in NC-AML. Though the exact function of MN1 in hematopoietic cells is unclear, it is another protein that is highly expressed in hematopoietic cells
n2:mentions
n3:16105979
Subject Item
_:vb5369394
rdf:type
n2:Context
rdf:value
In multivariate analysis, high MN1 expression was an independent prognostic marker [>>50<<].
n2:mentions
n3:16912223
Subject Item
_:vb5369395
rdf:type
n2:Context
rdf:value
High ERG expression is associated with the upregulation of many genes which are involved in cell proliferation, differentiation, and apoptosis [>>51<<]. The ERG gene is a recently identified molecular marker predicting adverse outcome of NC-AML patients. Over-expression of the ERG gene was first discovered in patients with complex karyotypes and abnormal chromosome 21 [34,52]. Marcucci,
n2:mentions
n3:16275934
Subject Item
_:vb5369396
rdf:type
n2:Context
rdf:value
Over-expression of the ERG gene was first discovered in patients with complex karyotypes and abnormal chromosome 21 [>>34<<,52]. Marcucci, et al showed that in patients less than 60 years old with de novo NC-AML, those patients expressing the highest levels of ERG (the top 25%) have a worse cumulative incidence of relapse (CIR) and OS. In this analysis, ERG
n2:mentions
n3:11979548
Subject Item
_:vb5369397
rdf:type
n2:Context
rdf:value
Over-expression of the ERG gene was first discovered in patients with complex karyotypes and abnormal chromosome 21 [34,>>52<<]. Marcucci, et al showed that in patients less than 60 years old with de novo NC-AML, those patients expressing the highest levels of ERG (the top 25%) have a worse cumulative incidence of relapse (CIR) and OS. In this analysis, ERG
n2:mentions
n3:15007164
Subject Item
_:vb5369398
rdf:type
n2:Context
rdf:value
Though more study is needed to confirm these results, ERG over-expression in NC-AML not only predicts an adverse clinical outcome, but also appears to be associated with a specific molecular signature [>>51<<].
n2:mentions
n3:16275934
Subject Item
_:vb5369399
rdf:type
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Patients with Down's syndrome are known to have a higher incidence of acute leukemia [>>53<<]. The high ERG expression may also be related to acute megakaryoblastic leukemia (FAB-M7) which is associated with trisomy 21 [54].
n2:mentions
n3:2149958
Subject Item
_:vb5369400
rdf:type
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rdf:value
The high ERG expression may also be related to acute megakaryoblastic leukemia (FAB-M7) which is associated with trisomy 21 [>>54<<].
n2:mentions
n3:16140924
Subject Item
_:vb5369401
rdf:type
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rdf:value
Two small studies conducted by Tse et al suggest that elevated AF1q expression is associated with poor outcomes both in pediatric AML and adult myelodysplastic syndrome (MDS) [>>55<<,56]. In the pediatric study, AF1q expression in AML patients varied from 0 to 154-fold compared with normal marrow and increasing AF1q expression level was associated with worsening survival with a hazard ratio of 1.02 per fold in AF1q
n2:mentions
n3:15217837
Subject Item
_:vb5369402
rdf:type
n2:Context
rdf:value
Two small studies conducted by Tse et al suggest that elevated AF1q expression is associated with poor outcomes both in pediatric AML and adult myelodysplastic syndrome (MDS) [55,>>56<<]. In the pediatric study, AF1q expression in AML patients varied from 0 to 154-fold compared with normal marrow and increasing AF1q expression level was associated with worsening survival with a hazard ratio of 1.02 per fold in AF1q
n2:mentions
n3:15638856
Subject Item
_:vb5369403
rdf:type
n2:Context
rdf:value
High AF1q expression was related to poor survival in univariate and multivariate models without association with any specific adverse cytogenetics [>>55<<]. The AF1q expression levels in the MDS study (total of 47 patients) suggested a statistically significant correlation with IPSS and AF1q expression level in high risk MDS [56]. Consistent with the findings in the pediatric AML study, MDS
n2:mentions
n3:15217837
Subject Item
_:vb5369404
rdf:type
n2:Context
rdf:value
The AF1q expression levels in the MDS study (total of 47 patients) suggested a statistically significant correlation with IPSS and AF1q expression level in high risk MDS [>>56<<]. Consistent with the findings in the pediatric AML study, MDS patients with high AF1q expression have an increased hazard ratio of death from MDS and relapse after allogeneic stem cell transplantation with correlation of specific poor
n2:mentions
n3:15638856
Subject Item
_:vb5369405
rdf:type
n2:Context
rdf:value
Additionally, gene-expression profiling has been applied to identify prognostically relevant subgroups [>>57<<].
n2:mentions
n3:15543237
Subject Item
_:vb5369406
rdf:type
n2:Context
rdf:value
For example, NC-AML patients were found to up-regulate class I homeobox A and B gene families [>>58<<]. In another study, DNA microarray experiments identified two distinct subgroups of NC-AML including one that was closely related to the gene signatures observed in AML with translocations. In this study, NC-AML patients in the
n2:mentions
n3:12696063
Subject Item
_:vb5369407
rdf:type
n2:Context
rdf:value
In this study, NC-AML patients in the "translocation-like" group had a superior prognosis to the other group [>>57<<]. Similarly, a separate study also found two distinct gene expression clusters in NC-AML patients with significantly different survival. Using a panel of 133 genes, it was possible to predict the clinical outcome of NC-AML patients [59].
n2:mentions
n3:15543237
Subject Item
_:vb5369408
rdf:type
n2:Context
rdf:value
Using a panel of 133 genes, it was possible to predict the clinical outcome of NC-AML patients [>>59<<]. NC-AML patients in the cluster with worse survival were more likely to harbor FLT3 mutations and were more commonly diagnosed with specific AML subtypes (FAB M1 and M2). Bullinger's observation was recently validated by a Cancer and
n2:mentions
n3:15084693
Subject Item
_:vb5369409
rdf:type
n2:Context
rdf:value
Bullinger's observation was recently validated by a Cancer and Leukemia Group B (CALGB) study that used a different microarray platform and had a longer follow up [>>60<<]. Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis [59]. In the future, gene expression profiling
n2:mentions
n3:16670265
Subject Item
_:vb5369410
rdf:type
n2:Context
rdf:value
Gene-expression profiling allows a comprehensive classification of AML that includes previously identified genetically defined subgroups and a novel cluster with an adverse prognosis [>>59<<]. In the future, gene expression profiling studies will likely play a role clinically in molecularly risk stratifying NC-AML patients as well as further elucidating the biology of NC-AML.
n2:mentions
n3:15084693
Subject Item
_:vb5369411
rdf:type
n2:Context
rdf:value
All of the six patients with positive quantitative real-time polymerase chain reaction (RQ-PCR) post-treatment eventually relapsed [>>33<<]. Real-time quantitative PCR has also been used to evaluate MRD in patients carrying NPM1 mutations at time of diagnosis. Decreasing NPM1 copy number correlated with response to therapy and in four cases followed post-therapy, rising copy
n2:mentions
n3:15921740
Subject Item
_:vb5369412
rdf:type
n2:Context
rdf:value
Decreasing NPM1 copy number correlated with response to therapy and in four cases followed post-therapy, rising copy number preceded hematological relapse [>>13<<]. Additional evaluation in the post-transplant setting showed that all patients who remained NPM1 mutant positive after transplant relapsed and all those who had increases in mutation copies post-transplant relapsed as well [61].
n2:mentions
n3:16541144
Subject Item
_:vb5369413
rdf:type
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rdf:value
Additional evaluation in the post-transplant setting showed that all patients who remained NPM1 mutant positive after transplant relapsed and all those who had increases in mutation copies post-transplant relapsed as well [>>61<<]. Comparison of CEBPα mutational status between diagnosis and relapse in AML was first investigated by Tiesmeier et al [62]. Two of 26 patients that relapsed had mutated CEBPα which persistent post-treatment suggesting a concordance
n2:mentions
n3:19100523
Subject Item
_:vb5369414
rdf:type
n2:Context
rdf:value
Comparison of CEBPα mutational status between diagnosis and relapse in AML was first investigated by Tiesmeier et al [>>62<<]. Two of 26 patients that relapsed had mutated CEBPα which persistent post-treatment suggesting a concordance between presentation and relapse. As approximately 60% of CEBPα mutations are insertion or deletions, they are an amenable to
n2:mentions
n3:14616999
Subject Item
_:vb5369415
rdf:type
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As approximately 60% of CEBPα mutations are insertion or deletions, they are an amenable to MRD monitoring by RQ-PCR [>>63<<]. One case study have also reported the utility of RT-PCR for detecting ERG MRD. The patient had a negative ERG fusion gene after transplant which then recurred at time of relapse [64]. A larger analysis of 19 patients conducted by Kong
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The patient had a negative ERG fusion gene after transplant which then recurred at time of relapse [>>64<<]. A larger analysis of 19 patients conducted by Kong et al. noted four types of TLS/FUS-ERG chimeric transcripts via RT-PCR. The transcripts were detectable at diagnosis as well as during remission and relapse suggesting resistance to
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The transcripts were detectable at diagnosis as well as during remission and relapse suggesting resistance to conventional chemotherapy [>>65<<]. Finally, RT-PCR has also been used to evaluate expression levels of partial tandem duplications in the MLL gene. Expression levels in 16 patients were analyzed at time of diagnosis and at relapse and found to be equivalent.
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Additionally, molecular relapse was detected 35 days before clinical relapse in two patients [>>39<<]. Thus, MLL-PTD was suggested as a target for MRD detection. Currently, MRD monitoring via these molecular markers is not commercially available to the community physician, but these studies provide insight to their future potential in
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