Adverse Prognostic Impact of GAS6 Expression in De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) (CALGB 8461, 9665, 20202; Alliance)

Abstract Abstract 1293 Receptor tyrosine kinases (RTKs) constitutively activated by gene mutation, overexpression and/or autocrine activation via ligand expression have been shown to negatively impact on outcomes of AML patients (pts). AXL, a member of the TAM (TYRO3, AXL, MERTK) RTK gene family was reported to be overexpressed and associated with poor survival in AML (Rochlitz, et al, Leukemia, 1999: 13:1352–8). No AXL mutations have been described, suggesting its activation may occur via aberrant expression in leukemic blasts of a TAM RTK ligand, GAS6. GAS6 was shown to be overexpressed in AML (Dirks, et al Leuk. Res. 23:643–51); yet its prognostic relevance is unknown. We report clinical and molecular associations and prognostic impact of aberrant GAS6 expression, in the context of TAM RTKs and known prognostic markers in de novo CN-AML pts (n=270; aged 18–83 y) treated with cytarabine/anthracycline-based therapies. Sixty-nine (26%) pts expressed GAS6 (>background signal; derived from microarray gene expression profiles of AML samples). TYRO3 expression status [positive (+) vs negative (–)] was similar in GAS6+ and GAS6– pts (P=.74), while AXL+ (P<.001) and low expression MERTK (P=.02) were more frequent in GAS6+ pts. Compared to GAS6– pts, GAS6+ pts were older (P=.02), had more platelets (P=.03), lower % blood blasts (P=.01) and increased frequency of hepatomegaly (P=.006); were more often NPM1 (P<.001) and CEBPA (P=.02) wild-type, and RUNX1 (P<.001) and ASXL1 (P=.002) mutated and expressed higher MN1 levels (P=.05). In univariable analyses, none of the TAM RTKs associated with complete remission (CR) and only TYRO3+ associated with reduced disease-free (DFS; P=.005), overall (OS; P=.005) and event-free survival (EFS; P=.008). GAS6+ vs GAS6– pts had lower CR rates (P<.001), shorter DFS (P=.03), OS (P=.004) and EFS (P<.001). While no TAM RTK entered the CR multivariable (MVA) model, GAS6+ expression status remained an independent marker for lower CR rate after adjusting for NPM1 status, white blood count (WBC) and age group (Table). In the DFS, OS and EFS models (Table), there was an interaction between GAS6 and the combined dual receptor (TYRO3/AXL) variable. GAS6 independently associated with shorter survival in TYRO3–/AXL– pts but not TYRO3+/AXL+ pts after adjusting for other variables. We show for the 1st time that GAS6 expression is an independent prognostic marker in CN-AML; negatively impacting on CR attainment, independent of TAM RTKs and on survival endpoints in pts lacking TYRO3 and AXL expression, regardless of MERTK expression. Our results suggest that GAS6 expressed by AML blasts plays a role in chemotherapy resistance. As GAS6 is expressed but not its RTKs in a subgroup of pts with poor outcome, this may lead to the hypothesis that the prognostic impact of GAS6 in those patients is mediated by the encoded ligand acting on cells other than AML blasts including, for example, natural killer cells, where activation of AXL RTK is reported to suppress innate immunity. Table. MVA models Variable CR DFS OS EFS P OR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) GAS6 expression, + v – .02 0.46 (0.24, 0.88) .03* 1.78 (1.07, 2.96) .05* 1.59 (1.00, 2.52) .03* 1.59 (1.06, 2.41) NPM1, mut v wt .001 2.97 (1.53, 5.77) – – – – .006 0.64 (0.46, 0.88) FLT3-ITD, present v absent – – .003 1.66 (1.19, 2.33) – – .005 1.55 (1.14, 2.11) WT1, mut v wt – – – – <.001 3.42 (1.97, 5.96) .03 1.84 (1.06, 3.18) RUNX1, mut v wt – – – – .002 2.00 (1.29, 3.10) – – ASXL1, mut v wt – – – – – – .003 1.66 (1.05, 2.60) DNMT3A  R882 mut v wt  Non-R882 v wt .006 .21 1.65 (1.15, 2.36) 1.33 (0.85, 2.08) WBC, continuous, 50 unit increase <.001 0.56 (0.41, 0.76) – – – – <.001 1.25 (1.12, 1.39) Age group, ≥ 60 y v < 60 y .01 0.40 (0.19, 0.83) <.001 2.09 (1.44, 3.03) <.001 2.64 (1.80, 3.87) <.001 2.16 (1.54, 3.02) OR, odds ratio; HR, hazard ratio; CI, confidence interval; mutated, mut; wild-type, wt. ORs > (<) 1.0 mean higher (lower) CR rate, and HRs > (<) 1.0 mean higher (lower) risk for relapse or death (DFS, EFS), respectively, for the higher values of the continuous variables and the first category listed for the categorical variables. Variables significant at α =.20 in univariable models were considered, although all considered variables are not shown. *There are interactions between GAS6 and TYRO3/AXL dual receptor status for DFS (P=.16), OS (P=.06) and EFS (P=.12). The P-values, HRs and CIs are for comparisons of GAS6+ v GAS6– pts within the TYRO3–/AXL– subset. Disclosures: No relevant conflicts of interest to declare.

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MiR-3151, a Novel MicroRNA Embedded in BAALC, Is Only Weakly Co-Expressed with Its Host Gene and Independently Impacts on the Clinical Outcome of Older Patients (Pts) with De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML)

Blood ◽

10.1182/blood.v118.21.1462.1462 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1462-1462

Author(s):

Ann-Kathrin Eisfeld ◽

Guido Marcucci ◽

Kati Maharry ◽

Sebastian Schwind ◽

Michael D. Radmacher ◽

...

Keyword(s):

De Novo ◽

Conflicts Of Interest ◽

Expression Profiles ◽

Strong Predictor ◽

Response To Therapy ◽

Host Gene ◽

White Blood Count ◽

Gene Transcript ◽

Prognostic Impact ◽

Expression Status

Abstract Abstract 1462 Despite progress made in understanding the biology and risk-adapted treatment of AML, prognosis of older pts [age ≥60 years (y)] remains poor. We have shown that high expression of the BAALC gene bestows worse outcome in older CN-AML pts. Yet, the mechanism(s) by which BAALC affects response to therapy remain unknown. MicroRNAs (miRs) are small noncoding RNAs that hybridize to target mRNAs and inhibit their translation or promote degradation, resulting in downregulation of the corresponding proteins. Recently, miR-3151 was discovered embedded in intron 1 of BAALC. We thus hypothesized that miR-3151 might be co-expressed with BAALC and contributes alone or in concert with its host to poor prognostic impact in older CN-AML. MiR-3151 and BAALC expression were measured by quantitative real time (RT) PCR in pretreatment blood of 179 older CN-AML pts enrolled on Cancer and Leukemia Group B (CALGB) cytarabine/daunorubicin-based protocols. The expression values of miR-3151 and BAALC were normalized to the internal controls SNORD44 and RN18S1, respectively. MiR-3151 expression correlated only weakly with the expression of BAALC (Spearman correlation r= 0.3). For clinical and prognostic analyses pts were dichotomized into high and low miR-3151 and BAALC expressers at the median miR and gene transcript expression values and analyzed for other molecular prognosticators (FLT3 -ITD, FLT3 -TKD, CEBPA, IDH1, IDH2, NPM1, TET2, WT1 mutations and ERG expression). Gene (GEP) and microRNA (MEP) expression profiles associated with miR-3151 expression were derived, using Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays, respectively. At diagnosis, higher miR-3151 expression was associated with lower % blood blasts (P =.02), FAB types M4 and M5 (P =.05), and wild-type NPM1 (P<. 001). High miR-3151 expressers had a lower complete remission (CR) rate (62% v 81%, P=. 005), and, with a median follow-up of 5.1 y for pts alive, shorter disease-free (DFS; hazard ratio [HR]=1.76, P=. 003; 3y rates, 7% v 26%; Figure 1A) and overall survival (OS; HR=1.86, P <.001; 3y rates, 10% v 32%; Figure 1B) than low expressers. In multivariable analyses (MVA), higher miR-3151 expression no longer remained in the model for CR after adjusting for BAALC expression and white blood count (WBC), but higher miR-3151 expression remained associated with shorter DFS (HR=2.32, P <.001), after adjusting for FLT3 -TKD, ERG expression status and WBC, and shorter OS (HR=1.77, P=. 003), after adjusting for ERG and BAALC expression status. To gain biological insights of miR-3151 -associated AML, we derived a GEP comprising 377 annotated genes and a MEP comprising 14 miRs. High miR-3151 expressers exhibited upregulation of genes associated with immature differentiation stage and adverse outcome (eg, MN1, ID1), downregulation of genes involved in hematopoietic differentiation (eg, MEIS1, PDCD4, PBX3) and transcriptional regulators (ZNF s, E2F3), including predicted targets of miR-3151 (eg, MEIS1). In the MEP, high miR-3151 expressers showed downregulation of let-7a/b/c that play crucial roles in cell cycle and proliferation regulation. While miR-3151- associated GEP/MEP shared genes with BAALC expression-associated GEP/MEP (eg, upregulated MN1 and DNTT and downregulated MEIS1, let-7b, miR-10a/b), other genes were unique to miR-3151- associated GEP/MEP (eg, upregulated ID1 and downregulated ZNFs, miR-206 and let-7a/c), suggesting biologic mechanisms distinct from those directly connected with BAALC upregulation operating in miR-3151- associated leukemia. In conclusion, high miR-3151 expression is independently associated with worse survival in older CN-AML pts. The weak correlation between expression of miR-3151 and its host gene BAALC, the independent impact of each on outcome endpoints (BAALC was a strong predictor of CR but did not predict DFS while miR-3151 was not independently associated with CR, but remained in the DFS MVA) and differences in GEP/MEP suggest that miR-3151 and BAALC are deregulated and contribute to disease outcome differently. We surmise that determining the expression levels of miR-3151 at diagnosis might help to improve the risk-stratification of older CN-AML. Development of therapies targeting miR-3151 upregulation with synthetic inhibitors may provide novel, effective strategies for personalized treatment of older CN-AML pts. Disclosures: No relevant conflicts of interest to declare.

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The Clinical Role of Micrornas (miRs) in Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML): miR-155 Upregulation Independently Identifies High-Risk Patients (Pts)

Blood ◽

10.1182/blood.v120.21.1387.1387 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1387-1387 ◽

Cited By ~ 1

Author(s):

Guido Marcucci ◽

Kati Maharry ◽

Klaus H. Metzeler ◽

Stefano Volinia ◽

Yue-Zhong Wu ◽

...

Keyword(s):

Clinical Outcome ◽

Conflicts Of Interest ◽

Disease Free Survival ◽

Gene Expression Signature ◽

White Blood Count ◽

Categorical Variables ◽

Prognostic Impact ◽

Continuous Variables ◽

Wild Type

Abstract Abstract 1387 miR-155 is upregulated in aggressive subtypes of solid tumors and leukemia. In AML, higher miR-155 expression is associated with FLT3-ITD. However, whether miR-155 upregulation impacts on clinical outcome independently from FLT3-ITD and other prognosticators is unknown. We evaluated the prognostic impact of miR-155 in 363 CN-AML pts (153 age <60 y; 210 age ≥60 y) that were treated with cytarabine-daunorubicin-based regimens and had a median follow-up of 7.9 y (range, 2.3–12.9). miR-155 levels were measured in pretreatment marrow or blood by the NanoString nCounter assay quantifying expression of the encoding gene MIR155HG; other molecular markers were assessed centrally. High miR-155 expressers (miR-155) had higher WBC (P<.001) and were more often FLT3-ITD-positive (pos; P<.001), RUNX1-mutated (mut; <.001), WT1-mut (P=.03), ↑ ERG (P=.02) and ↑ BAALC (P=.002), and less often CEBPA-mut (P=.003), IDH2-mut (P=.004) and FLT3-TKD-pos (P=.08) than low expressers (↓ miR-155). ↑ miR-155 had lower CR rates (P<.001), shorter DFS (P=.001) and OS (P<.001), than ↓ miR-155. In multivariable analyses (MVA; Table), ↑ miR-155 was associated with lower CR rates (P=.007) and shorter OS (P<.001). Among younger pts, ↑ miR-155 had lower CR rates (P=.03) and shorter DFS (P<.001) and OS (P<.001) than ↓ miR-155. In MVA (Table), ↑ miR-155 status remained associated with worse CR rate (P=.06), shorter DFS (P=.003) and OS (P=.01). Among older pts, ↑ miR-155 had lower CR rates (P=.008) and shorter OS (P<.001); in MVA (Table), ↑ miR-155 remained associated with worse CR (P=.03) and shorter OS (P=.05). In the European LeukemiaNet classification, younger ↑ miR-155 in the Favorable (Fav) Genetic Group (GG; CEBPA-mut and/or NPM1-mut without FLT3-ITD) had lower CR rates (P=.03) and shorter DFS (P=.04) and OS (P=.02) than ↓ miR-155. In the younger Intermediate-I (Int-I) GG pts (with wild-type CEBPA, NPM1-mut with FLT3-ITD, or wild-type NPM1), miR-155 expression did not impact independently on outcome. In older pts, ↑ miR-155 had a shorter OS both in the Fav (P=.06) and Int-I GGs (P=.05) than ↓ miR-155. To gain biologic insights, we derived an Affymetrix gene-expression signature that comprised 196 mRNAs significantly correlated with miR-155 expression. Consistent with previous mechanistic studies, Gene Ontology analysis revealed that the ↑ miR-155-associated signature was enriched for genes involved in anti-apoptotic, proliferative and inflammatory activities (FDR<0.05). ↑ miR-155 was not significantly correlated with that of any other microRNAs (miRs) thereby supporting the unique role of miR-155 among the miRs in AML. In summary, miR-155 expression is independently associated with clinical outcome in CN-AML and may allow for better evaluation of molecular risk, especially in pts lacking FLT3-ITD, like those in the ELN Fav GG. Moreover, given its role in deregulation of fundamental mechanisms of cell homeostasis and the emergence of miR inhibitors, miR-155 may become a novel therapeutic target. Table. MVA in pts with primary CN-AML Group CR DFS OS OR P HR P HR P All pts miR-155 expression not significantly associated with DFS a miR-155, ↑ v ↓ 0.46 .007 1.62 <.001 NPM1, mut v wt 2.42 .005 BAALC, ↑ v ↓ 0.37 .002 2.16 <.001 WBC, each 50 units 0.65 <.001 Age group, older v younger 0.43 .003 2.38 <.001 FLT3-ITD, pos v neg 1.78 <.001 Race, white v nonwhite 1.62 .03 Pts age < 60 y miR-155, ↑ v ↓ 0.39 .06 2.13 .003 1.84 .01 RUNX1, mut v wt 0.21 .01 Age, each 10 y increase 0.45 .004 WBC, each 50 units 1.49 <.001 FLT3-ITD, pos v neg 2.82 <.001 1.82 .01 FLT3-TKD, pos v neg 3.27 <.001 BAALC, ↑ v ↓ 2.66 <.001 2.33 <.001 Race, white v nonwhite 2.81 .02 CEBPA, mut v wt 0.47 .02 WT1, mut v wt 2.25 .005 Pts age ≥ 60 y miR-155 expression not significantly associated with DFS miR-155, ↑ v ↓ 0.46 .03 1.36 .05 NPM1, mut v wt 2.45 .03 BAALC, ↑ v ↓ 0.32 .004 2.18 <.001 WBC, each 50 units 0.65 .005 Age, each 10 y increase 0.48 .02 FLT3-ITD, pos v neg 1.56 .006 ↑, high expression; ↓, low expression; CR, complete remission; DFS, disease-free survival; HR, hazard ratio; mut, mutated; neg, negative; OR, odds ratio; OS, overall survival; pos, positive; WBC, white blood count; wt, wild-type. Odds ratios > (<) 1.0 mean higher (lower) CR rate and HRs > (<) 1.0 mean higher (lower) risk of relapse or death (DFS) or death (OS) for the higher values of continuous variables and the 1st category listed for categorical variables. Disclosures: No relevant conflicts of interest to declare.

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Assessment of CEBPA Mutations Might Contribute to a Better Prognostic Assignment in Patients with Intermediate-Risk Cytogenetics Acute Myeloid Leukemia (AML).

Blood ◽

10.1182/blood.v114.22.2611.2611 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2611-2611

Author(s):

Marta Pratcorona ◽

Montserrat Torrebadell ◽

Neus Villamor ◽

Maria Rozman ◽

Mireia Camós ◽

...

Keyword(s):

De Novo ◽

Conflicts Of Interest ◽

Complete Response ◽

Prognostic Impact ◽

Single Mutation ◽

Intermediate Risk ◽

Wild Type ◽

Male Predominance ◽

Cebpa Mutations ◽

Wbc Count

Abstract Abstract 2611 Poster Board II-587 The prognostic heterogeneity of patients with intermediate-risk cytogenetics AML (AML-IR) is mostly clarified by determination of mutations of NPM1 gene (NPMmut) and internal-tandem duplication of FLT3 gene (FLT3-ITD). Nonetheless, other genetic lesions described in this population might contribute to a better prognostic categorization. In this context, we analyzed the presence of CEBPA mutations and associated features in patients with AML-IR lacking both NPMmut and FLT3-ITD. Overall, 136 patients (51% female; median age: 53, range: 17=74) diagnosed with de novo AML-IR (MRC definition) in our institution between 1994 and 2008 who received standard AML chemotherapy were included in the analysis. CEBPA mutations (CEBPAmut) were investigated by whole gene sequencing using 4 primer pairs according to previously reported methods (Fröhling et al, 2004). Sixty-five patients (48%) harbored NPM1 mutations, 30 of them having concomitant FLT3-ITD. Among NPM1 wild-type patients (NPMwt), FLT3-ITD, CEBPA and MLL mutations were detected in 18, 11, and 5 patients, respectively. Regarding cases with CEBPAmut, biallelic mutations were found in 8 patients, including 6 cases with combined mutations of N-terminal and bZIP domains and two homozygous mutations, whereas a single mutation in bZIP domain was found in the three remaining patients. As compared to patients with wild-type CEBPA (CEBPAwt), those with CEBPAmut were younger (29 vs. 53, p=0.027), and showed a trend to male predominance (73 vs. 46%, p=0.09) and lower WBC count at presentation (16 vs. 33.5 × 109/L, p=.095). Of note, CD7 antigen was aberrantly expressed in virtually all CEBPAmut cases (10/11), compared to only 21% of CEBPAwt patients (p<0.001). Moreover, an abnormal karyotype was observed in 4 patients with CEBPAmut. In the overall series, complete response rate (CR), survival (OS), and relapse incidence (RI) were 83%, 39±4% (5-yr), and 50±5% (5-yr), respectively. Independent favorable factors for survival were younger age (<median; RR: 1.9, 95% CI: 1.2-3, p=0.004), low WBC count at diagnosis (< median; RR: 1.7, 95% CI: 1.1–2.6, p=0.025) and NPMmut/FLT3-ITDneg status (RR: 2.4, 95% CI: 1.3–4.2, p=0.003). Remarkably, patients with CEBPAmut showed a favorable outcome, with a trend for a more prolonged survival, compared to patients with a high-risk NPM/FLT3 status (5-year OS in pts <60 years: 74±16% vs. 33±6%, p=0.087). Based on these results, patients were grouped in a favorable (i.e., either NPMmut /FLT3-ITDneg or CEBPAmut, FAV) or unfavorable molecular category (i.e., those with FLT3-ITD, double NPMwt and CEBPAwt configuration, or MLL abnormalities, UNFAV); these two groups had independent prognostic impact on OS (RR: 2.3, 95% CI: 1.3–4, p=0.001; see figure), RI (RR: 2.2, 95% CI: 1.2–4.3, p=0.016), and leukemia-free survival (RR: 2.2, 95% CI: 1.3–3.7, p=0.002). Importantly, the outcome of patients in the FAV group did not differ according to post-remission treatment (autologous vs. allogeneic stem-cell transplantation, SCT), whereas relapse risk was significantly higher in patients with unfavorable markers who received autologous SCT (60±13% vs. 18±12%, p=0.03). In summary, the assessment of CEBPA mutations, especially in patients lacking NPMmut and FLT3-ITD and expressing CD7 antigen, may refine the molecular prediction of prognosis and guide therapeutic strategy in patients with intermediate-risk AML. Disclosures: No relevant conflicts of interest to declare.

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Comparison of Clinical and Biologic Significance of WT1 Mutations in Populations of Older (≥60 years[y]) and Younger (<60 y) Adult Patients (Pts) with Cytogenetically Normal (CN) De Novo Acute Myeloid Leukemia (AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽

10.1182/blood.v114.22.326.326 ◽

2009 ◽

Vol 114 (22) ◽

pp. 326-326

Author(s):

Heiko Becker ◽

Guido Marcucci ◽

Kati Maharry ◽

Michael D. Radmacher ◽

Krzysztof Mrózek ◽

...

Keyword(s):

Gene Expression ◽

De Novo ◽

Age Groups ◽

Stem Cell Marker ◽

Treatment Intensity ◽

Prognostic Impact ◽

Wild Type ◽

Age Related ◽

Exon 9 ◽

Wt1 Mutation

Abstract Abstract 326 Mutations of the Wilms tumor (WT1) gene are found in ∼10% of younger (<60 years[y]) adult pts with de novo CN-AML and impact adversely on their outcome. The clinical significance of WT1 mutations has not yet been evaluated in older (≥60 y) CN-AML pts. Therefore, we analyzed frequency and clinical impact of WT1 mutations in the context of other molecular markers in a relatively large cohort of 243 pts ≥60 y (range, 60-83 y) with de novo CN-AML treated intensively on upfront cytarabine/daunorubicin-based CALGB protocols. Included pts were those with material available for analysis of WT1 mutation status and that of a panel of other validated molecular prognosticators including NPM1, FLT3 (ie, FLT3-ITD, FLT3-TKD) and CEBPA mutations, BAALC and ERG expression levels. Mutations in WT1 “hot spots” (exons 7 and 9) were assessed by DHPLC and sequencing. The results were compared with the findings in younger (18-59 y) CALGB pts (n=207) characterized molecularly in a similar fashion. Gene expression profiles in both populations were assessed centrally using Affymetrix U133 plus 2.0 microchip. Among the 243 older pts, 16 (7%) had WT1 mutations. Of those, 14 had single WT1 mutations in exon 7 [frameshift (n=8), nonsense (n=1), and missense (n=1)] or in exon 9 [missense (n=4)]; 1 pt had 2 frameshift mutations in exon 7, and 1 had 1 frameshift mutation in exon 7 and 1 missense mutation in exon 9. Compared with older WT1 wild-type pts, older WT1 mutated pts more often had FLT3-ITD (P<.001) and had lower hemoglobin (P=.01), and higher WBC (P=.03) and % blood blasts (P=.03). WT1 mutated pts had a trend for lower complete remission (CR) rates (50% v 70%, P=.16) and shorter OS (P=.08; Figure 1), but similar disease-free survival (DFS; P=.59; Figure 2) compared with WT1 wild-type pts. The frequency of WT1 mutations tended to be lower in older than younger pts (7% v 12%, P=.07). Mutation types and pretreatment clinical and molecular characteristics associated with WT1 mutations were similar between the two age groups. Despite differences in treatment intensity, there were no significant differences in younger v older WT1 mutated pts with regard to CR rates (P=.18), or OS (P=.68; Figure 1) or DFS (P=.66; Figure 2) durations. In contrast, younger WT1 wild-type pts had significantly higher CR rates (P<.001), and longer OS (P<.001; Figure 1) and DFS (P<.001; Figure 2) than older WT1 wild-type pts. Although associated with WT1 mutations in both the younger (P=.02) and older age groups, FLT3-ITD had no impact on CR rates (P=.28), or OS (P=.15) or DFS (P=.21) durations of all WT1 mutated pts after controlling for age-related treatment intensity. To provide insights into the molecular features associated with WT1 mutations we analyzed the whole cohort (younger and older) for genes differentially expressed (ie, P≤.001) between WT1 mutated and WT1 wild-type pts. A signature comprising 110 named genes was derived. Among the 71 upregulated genes in WT1 mutated pts, were those encoding the leukemia stem cell marker CD96 and the leukemia fusion protein partners PML and MLL. The most upregulated gene (6.2 fold) was GTSF1, which, like WT1, may be involved in germ cell development. Among the 39 genes downregulated in WT1 mutated pts, were those encoding SNRPN and SNURF, involved in pre-mRNA processing, and the insulin receptor and IRS2, upstream effectors of the PI3K/AKT pathway. In conclusion, WT1 mutations in older CN-AML pts are less frequent than in younger pts. While WT1 mutations independently associate with shorter OS and DFS in younger CN-AML pts, in older CN-AML pts they are only associated with trends for a worse CR rate and shorter OS. This difference appears due to the poor outcome of the older compared to younger WT1 wild-type pts, which reduced the prognostic impact of WT1 mutations in the former. Nevertheless, the outcome of pts with WT1 mutations is equally poor in older and younger pts regardless of differences in treatment, thereby suggesting that WT1 mutated CN-AML may constitute a distinct biologic entity across age groups. The unique gene expression signature associated with WT1 mutations could provide useful insights into WT1 mutation-driven leukemogenic mechanisms across age-related groups, and help in devising novel molecular targeted therapeutic approaches for this subtype of CN-AML. Disclosures: No relevant conflicts of interest to declare.

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An Insertional Mutagenesis Screen for Genes That Cooperate with Mll-AF9 in Leukemogenesis.

Blood ◽

10.1182/blood.v114.22.3962.3962 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3962-3962

Author(s):

Rachel Joy Bergerson ◽

Lara S Collier ◽

Sanne Lugthart ◽

Raha Allaei ◽

Molly J Nixon ◽

...

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Latency Period ◽

Wild Type ◽

Aberrant Expression ◽

Genetic Pathways ◽

Elevated Expression ◽

Insertion Sites ◽

Murine Leukemia

Abstract Abstract 3962 Poster Board III-898 By altering the activity of specific transcription complexes, the MLL-AF9 fusion oncogene can initiate the process of acute myeloid leukemia (AML) development. However, all the genetic pathways that can cooperate with MLL-AF9 expression to cause full-blown AML are unknown. These pathways will provide therapeutic targets for MLL-AF9-associated AML. Mice with constitutive expression of the Mll-AF9 fusion oncoprotein under the control of the endogenous promoter develop AML but only after a prolonged latency. This model thus provides a system for understanding the evolution of AML initiated by an MLL fusion oncoprotein. We hypothesized that infection with a recombinant Murine Leukemia Virus, abbreviated M4070, could cooperate with MLL-AF9 expression to accelerate the onset of leukemia by causing the secondary mutations required for cancer progression. We bred Mll-AF9 heterozygous males to wild type females, and the offspring were injected at three days of age with M4070 virus (n=211) or were mock infected (n=68). All mice were genotyped and observed for disease progression. Virally infected Mll-AF9/+ mice succumb to disease with a significantly reduced latency period when compared to virally infected wild type (WT) mice (p < .0001) and uninfected Mll-AF9/+ mice (p < .0001), indicating that M4070 infection causes significant leukemia acceleration in these mice. Histopathology, immunohistochemical staining, analysis of the surface immunophenotype by flow cytometry, and Southern blot analysis of T and B cell receptor rearrangement indicated that infected Mll-AF9/+ animals developed primarily myeloid leukemia (myeloperoxidase positive, Mac1 or Mac1/Gr1 positive, CD3 negative) while infected WT animals developed mostly lymphoid leukemia (CD3 positive, CD4 and/or CD8 positive, myeloperoxidase negative). Retroviral insertion sites were cloned from 167 leukemic tissues from the accelerated leukemia mice using two different restriction enzymes in a shotgun-based, linker-mediated, cloning protocol to identify the genes most frequently mutated in Mll-AF9 positive leukemia. More than 4,100 independent insertions were isolated and 101 common insertion sites (CIS), defined as genomic locations with several proviral insertions from at least 3 mice, were identified. The majority of the CIS harbored proviral insertions in both Mll-AF9/+ and wild type mice, but a subset of CIS were found in only one group or the other. Some of the genes closest to the CIS have been identified as target genes in other proviral screens and some are known cancer genes. We studied a subset of the CIS-associated genes for aberrant expression in leukemic tissues. There was elevated expression of Mn1, and a trend towards increased expression of Bcl11a and Fosb, in our Mll-AF9 murine leukemia samples with proviral insertions nearby these genes. Moreover, elevated expression of MN1, FOSB, and BCL11A has been observed in microarray studies of human patients with AML. We have completed a bone marrow transduction/transplantation experiment to seek functional evidence of cooperation with Mll-AF9. Mice transplanted with Mll-AF9/+ bone marrow that had been transduced with a retrovirus encoding the candidate gene MN1 succumb to myeloid malignancy faster than mice transplanted with wild type bone marrow transduced with MN1, or Mll-AF9/+ bone marrow transduced with a retrovirus encoding just the Green Fluorescent Protein gene. This data suggests that MN1 can cooperate with Mll-AF9 to accelerate myeloid leukemia in a mouse model. We are currently using shRNA knockdown strategies in human cell lines to confirm cooperation of more candidate genes with MLL-AF9 in AML development. Thus, CIS-associated genes from leukemias accelerated by M4070 in Mll-AF9/+ mice may help define important genetic pathways that are altered during progression of AML induced by MLL fusion oncogenes. Disclosures: No relevant conflicts of interest to declare.

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Disruption of the ASXL1 Gene Is Prevalent In PMF: Analysis of Molecular Genetics and Clinical Phenotypes

Blood ◽

10.1182/blood.v116.21.3074.3074 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3074-3074

Author(s):

Brady L Stein ◽

Donna M Williams ◽

Michael A McDevitt ◽

Christine L. O'Keefe ◽

Ophelia Rogers ◽

...

Keyword(s):

Molecular Genetics ◽

De Novo ◽

Conflicts Of Interest ◽

Single Nucleotide Polymorphism Array ◽

Myeloproliferative Neoplasms ◽

Direct Sequencing ◽

Snp Array ◽

Uniparental Disomy ◽

Jak2 V617f ◽

Wild Type

Abstract Abstract 3074 Background: The myeloproliferative neoplasms, PV, ET and PMF, share phenotypic features and molecular lesions, yet PMF distinguishes itself by its unfavorable natural history and rate of leukemic evolution. These distinctions may occur as a result of cooperating genomic lesions specific to PMF compared to PV or ET. We performed single nucleotide polymorphism array (SNP-A)-based karyotyping in 210 MPN patients and identified 20q11 deletions in 10% of PMF cases and in none of the PV or ET cases. The 20q11 deletion region spanned 1,662 KB and encompassed 37 genes, of which ASXL1 was included. To test whether ASXL1 contained lesions in the MPN cohort at large, we directly sequenced key regions of the ASXL1 gene in 65 PMF, 11 PV and 14 ET cases, as well as 7 controls from the SNP-array cohort. Genomic DNA from neutrophils and in select cases, purified CD34+ cells was used for both SNP-A and direct sequencing. Clinical parameters were correlated with genomic findings and the quantitative JAK2 V617F neutrophil allele burden Molecular genetics: 26/65 (40%) of PMF cases had abnormalities in ASXL1 (4 deletions, 22 mutations) whereas none of the 32 PV, ET or control cases had such lesions. The majority of ASXL1 sequence variations were nonsense lesions including the previously reported 1934dupG which comprised 30% of all of the mutations. The residual ASXL1 allele in all 20q11 deletion cases containing the ASXL1 gene was intact. In three PMF cases, more than one distinct ASXL1 mutation was identified, and cloning experiments on two of those cases indicated that the lesions were biallelic. Using banked samples, we observed the acquisition of an ASXL1 lesion over time, and established that ASXL1 lesions detected in 2 post ET-MF cases were also detected at low levels in the ET phase of the MPN. Genotype/Phenotype Correlations: ASXL1 deletions and mutations were prevalent in de novo PMF (37%), post PV-PMF (20%) post ET-PMF (62%) and in PMF/AML (33%). ASXL1 mutations did not associate with chemotherapy exposure as the prevalence of hydroxyurea use was similar in patients with and without mutations, and ASXL1 –mutation positive cases were present in patients who had never received any form of chemotherapy. There was no dependence upon JAK2 status as the presence of ASXL1 mutations were identified in JAK2 V617F-negative cases (9/26); JAK2 V617F-heterozygous cases (10/26); and JAK2 V617F-homozygous cases (7/26). Based on results of SNP-A, patients with ASXL1 mutations were equally as likely to have uniparental disomy (involving 9p or other regions) and loss/gain abnormalities (>1MB) compared to those without ASXL1 mutations. There were no differences in sex, age, or disease duration between PMF patients with and without ASXL1 mutations. In the ASXL1-mutant group, there was a trend toward a lower median white blood cell count (8 vs. 12.5 k/cu mm; p=0.3) and hemoglobin (9.7 vs. 11 g/dl; p=0.3) compared to ASXL1-wild-type patients. Furthermore, those PMF patients with ASXL1 mutations were significantly more likely to have received anemia-directed therapy (transfusion, erythropoietin, immunomodulating agents, steroids) compared to those without mutations (15/26 (58%) vs. 11/39 (23%); p=0.02). Post ET-MF patients comprised 31% (8/26) of ASXL1-mutant cases, compared to only 10% (4/39) ASXL1- wild-type cases (p=0.03). However, the presence of an ASXL1 mutation did not associate with an accelerated transition rate from ET to MF; among the 12 post ET-MF cases in the cohort, the median time of transition from ET to MF was 15.5 years in those with ASXL1 mutations compared to 7 years in those with ASXL1 wild-type status (p=0.02). Conclusion: Disruption of the ASXL1 gene occurs in 40% of PMF cases. The association of ASXL1 lesions, due to either mutation or deletion, suggests that ASXL1 haplo-insufficiency is associated with a PMF phenotype in the context of other known and unknown lesions, and that disruption of ASXL1 function may directly contribute to the pathophysiology and clinical complications of primary and secondary myelofibrosis. These data support the concepts that cooperative lesions in addition to JAK2 V617F are critical in generating PMF, that PMF is molecularly more complex than either PV or ET, and that the transition of PV or ET to PMF is associated with the acquisition of genomic lesions, such as ASXL1, that are present in PMF at large. Disclosures: No relevant conflicts of interest to declare.

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Negative Effects of GM-CSF Signaling In t(8;21)-Induced Leukemia

Blood ◽

10.1182/blood.v116.21.3163.3163 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3163-3163

Author(s):

Shinobu Matsuura ◽

Ming Yan ◽

Eun-Young Ahn ◽

Miao-Chia Lo ◽

David Dangoor ◽

...

Keyword(s):

Myeloid Leukemia ◽

Sex Chromosome ◽

De Novo ◽

Conflicts Of Interest ◽

Hematopoietic Cells ◽

Receptor Activation ◽

Pseudoautosomal Region ◽

Wild Type ◽

Gm Csf

Abstract Abstract 3163 The t(8;21)(q22;q22) translocation is one of the most common chromosomal translocations in de novo acute myeloid leukemia (AML). The 8;21 translocation is often associated with additional cytogenetic abnormalities. The loss of the sex chromosome (LOS) is by far the most frequent abnormality found in association with the t(8;21) leukemia, accounting for 32–59% of patients, in contrast to other types of AML in which the LOS occurs in less than 5% of patients. To evaluate the role of sex chromosome deletion in t(8;21)-related leukemogenesis, hematopoietic cells from a mouse line with only one sex chromosome were used in retrovirus-mediated t(8;21) (AML1-ETO) expression and transplantation assays. The absence of leukemia in those animals suggested that a gene present in the pseudoautosomal region of sex chromosomes in humans but not in mice may be the target gene in LOS. The granulocyte-macrophage colony-stimulating factor receptor α (GM-CSFRα) gene is one such gene and is also known to be involved in myeloid cell survival, proliferation and differentiation. The GM-CSFRα gene is specifically down-regulated in AML patients with t(8;21), but not in other common translocations (Valk PJM et al, NEJM, 2004). The GM-CSFR complex is composed of α and βc subunits that assemble into a complex for receptor activation and signaling. To investigate the role of GM-CSFR signaling in t(8;21)-mediated leukemogenesis, GM-CSFR common β subunit knockout (GM-CSFRβc-/-) mice were used in our studies as a model for deficient GM-CSFR signaling. Transduction of AML1-ETO in hematopoietic cells from GM-CSFRβc-/- resulted in myeloid leukemia of a median survival time of 225 days, high percentage of blasts in peripheral blood and bone marrow, anemia, thrombocytopenia, hepatomegaly and splenomegaly. Comparison of wild-type and GM-CSFRβc-/- cells in the same transplantation resulted in development of AML1-ETO-induced leukemia at higher penetrance in GM-CSFRβc-/- cells (28.5% vs 100%). Moreover, the latency of leukemia was shorter in GM-CSFRβc-/- cells than in wild-type cells after transduction of AML1-ETO9a. Analysis of the hematopoietic compartment of healthy GM-CSFRβc-/- mice detected no significant abnormalities in the immature hematopoietic compartment (LSK, CMP, GMP, MEP), suggesting that AML1-ETO expression is required for leukemia to occur. In vitro, expression of AML1-ETO alone is sufficient for the immortalization of normal hematopoietic cells, as demonstrated by serial replating capacity of cells in methylcellulose colony assay. Addition of mGM-CSF to the basic cytokine cocktail (mIL-3, hIL-6, mSCF, hEPO) did not significantly affect number, type, size, and cell composition of colony cells. In contrast, the addition of mGM-CSF eliminated the replating capacity of AML1-ETO expressing cells, although they survived longer than control vector-infected cells. The results suggest that activation of GM-CSF signaling can specifically abrogate the self-renewal ability of potential leukemic stem cells in the early immortalization phase. These results support a possible tumor suppressor role of GM-CSF in leukemogeneis by AML1-ETO and may provide clues to understand how AML1-ETO corrupts normal GM-CSF signals to its own advantage for leukemogenic transformation. Disclosures: No relevant conflicts of interest to declare.

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Analysis of ASXL1, IDH1, IDH2, c-CBL, and WT1 Mutations in De Novo Acute Myeloid Leukaemia

Blood ◽

10.1182/blood.v118.21.1450.1450 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1450-1450

Author(s):

Mariam Ibañez ◽

Esperanza Such ◽

Jose Cervera ◽

Irene Luna ◽

Sandra Dolz ◽

...

Keyword(s):

De Novo ◽

Prognostic Impact ◽

Significant Implication ◽

Wild Type ◽

Idh Mutations ◽

Flt3 Mutations ◽

Exon 4 ◽

De Novo Aml ◽

Cebpa Mutations ◽

Acute Myeloid

Abstract Abstract 1450 The clinical relevance and prognostic implications of some recently identified mutations in acute myeloid leukemia (AML) is not yet well established. Among them, we have selected to be analyzed those affecting the following genes: Additional Sex Combs-Like 1 (ASXL1), Isocitrate Dehydrogenase (IDH1 and IDH2), Casitas B-lineage Lymphoma (c-CBL), and Wilms Tumor 1 (WT1). They have been previously reported with a variable incidence: ASXL1 mutations in 10.8% patients with normal karyotype (NK), IDH1 and IDH2 mutations in 8 – 33% of de novo AML, c-CBL mutations in 2% of de novo AML, and WT1 mutations in 5–12% of de novo AML patients. In order to know the incidence and prognostic impact of these mutations and their possible cooperative role in leukemogenesis, we have screened for ASXL1, IDH1, IDH2, c-CBL, WT1, FLT3, NPM1 and CEBPa, mutations in a cohort of de novo AML patients from a single centre. We studied 174 de novo AML patients [98M/76F; median age: 62 yr. (range: 16 – 88); favourable (n= 13), intermediate (n= 86) and high (n= 51) cytogenetic risk classification by the MRC group]. DNA was isolated from bone marrow samples obtained at diagnosis. In order to determine cooperating mutations, we developed a new combination of high-resolution melting (HRM) assays on a LightCycler® 480 and lastly direct sequencing, to detect somatic mutations for ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), WT1 (exons 7, 8 and 9) and c-CBL (exons 8 and 9). All mutations reported in this study were confirmed al least twice. FLT3 (ITD and D835Y), NPM1 (exon 12) and CEBPa were performed as described previously by standard methods. Sequence analysis was checked by its corresponding GeneBank Accession Number. The number of patients found to carry mutations in our series was: 16 patients with ASXL1 mutations (9.2%), 16 patients with IDH mutations (2.9% had a IDH1R132, 12.6% the SNP rs11554137 and 6.3% IDH2R140), 5 patients with WT1 mutations (2.9%), 37 patients with FLT3 mutations (21.3%), 44 patients with NPM1 mutations (25,3%) and 8 patients with CEBPa mutations (4.6%). No mutations where found in c-CBL. We could not found a pattern of cooperating mutations in the studied group of genes. WT1, FLT3 and NPM1 were associated with leukocyte count >30 × 109/L at diagnosis (80% vs. 31% for WT1, P =0,022; 68% vs. 22% for FLT3, P= 0.001; and 50% vs. 24% for NPM1, P= 0.002; in mutated vs. wild-type patients, respectively). WT1 was also associated with a platelet count > 50 × 109/L at diagnosis (100% vs. 57% in mutated vs. wild-type patients, respectively; P =0,048). Besides, FLT3 and NPM1 mutations were more frequent in the intermediate cytogenetic risk group (82% and 74%; P =0.004 and P =0.047; respectively). ASXL1 and IDH mutations were not correlated with any of the clinical and biological features studied. In univariate analysis, only age and cytogenetics had an impact on overall survival (OS, median of 12mo vs. 3mo, for patients < and ≥65 yr., P <0.001 and 24mo, 11mo and 3mo for favourable, intermediate and high risk, P =0.005). Mutational status of ASXL1, IDH1, IDH2, WT1, FLT3, NPM1 and CEBPa did not impact on outcome in the whole series. However, when the analysis was restricted to patients with intermediate cytogenetic risk, patients with FLT3 mutations had a shorter OS (19mo vs. 8mo, wild-type vs. mutated patients; P =0.047) and those with WT1 mutations showed a trend towards an inferior OS (11mo vs. 1mo, wild-type vs. mutated patients; P = 0.066). In multivariate analysis in patients with intermediate cytogenetic risk, the age [HR (95% CI) = 3.3 (1.9 − 5.9) P <0.001], and FLT3 status [HR (95% CI) = 2.2 (1.2–3.9) P =0.008] retained an independent adverse significance for OS. In terms of relapse free survival any of the variables showed a significant implication. To sum up, the incidence found for the studied genes was lower than the previously reported: ASXL1, 9.2%; IDH1R132, 2.9%; IDH2R140, 6.3%; WT1, 2.9%; and c-CBL, 0%. We were unable to find a pattern of cooperating mutations in the studied group of genes or any impact of these mutations on the outcome. Disclosures: No relevant conflicts of interest to declare.

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AML with Recurrent Genetic Abnormalities and AML with Myelodysplasia-Related Changes Account for Three-Quarters of Previously Untreated Pediatric AML-the Results of a Nation-Wide Central Review in Japan-

Blood ◽

10.1182/blood.v118.21.4899.4899 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4899-4899

Author(s):

Akitoshi Kinoshita ◽

Hayato Miyachi ◽

Hiromichi Matsushita ◽

Tomohiko Taki ◽

Miharu Yabe ◽

...

Keyword(s):

Who Classification ◽

De Novo ◽

Conflicts Of Interest ◽

Prognostic Significance ◽

Prognostic Impact ◽

Genetic Abnormalities ◽

Precise Diagnosis ◽

De Novo Aml ◽

Pediatric Aml ◽

Mixed Phenotype

Abstract Abstract 4899 [Background] The WHO classification has been widely accepted among physicians who are engaged in treating pediatric AML patients. In 2008, the revised WHO classification has expanded the two categories in AML; AML with recurrent genetic abnormalities and AML with myelodysplasia-related changes. The epidemiology and prognostic significance of these refined categories remains to be explored in children. [Methods] JPLSG AML-05 is a nationwide clinical trial for children with de novo AML, excluding acute promyelocytic leukemia and myeloid leukemia with Down syndrome, which was conducted between November 2006 and December 2010 in Japan. A central review of diagnosis based on the WHO classification was prospectively performed on each case soon after morphological, cytogenetical and immunological data were submitted to data center. Regarding the cases with discrepant results among these parameters, further diagnostic tests including FISH and chimera gene analyses were underwent to confirm the diagnoses. [Results] Four hundred and eighty four patients were enrolled in the study. Thirty patients did not meet the criteria of AML. We could not collected suitable data for diagnosis in 6 patients. Regarding the rest 448 patients, diagnoses based on the WHO classification 2001 and 2008 were determined. According to the 2001 version, 227 (50.6%) had AML with recurrent genetic abnormalities:124 (27.7%) of AML with t(8;21)(q22;q22);(AML1/ETO ), 32 (7.1%) of AML with inv(16)(p13q22); (CBFβ/MYH11), 38 (8.5%) of AML with t(9;11)(p22;q23), and 33 (7.4%) of AML with the other11q23 (MLL) abnormalities, 36 (8.0%) had AML with multilineage dysplasia, and 185 (41.3%) had AML, not otherwise categorized. According to 2008 version, 235 (52.5%) had AML with recurrent genetic abnormalities: 124 (27.7%) of t(8;21)(q22;q22);(AML1/ETO ), 32 (7.1%) of AML with inv(16)(p13q22); (CBFβ/MYH11), 38 (8.5%) of AML with t(9;11)(p22;q23), 33 (7.4%) of AML with the other11q23 (MLL) abnormalities,4 of AML with t(6;9)(p23;q34);DEK-NUP214,2 of AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2);RPN1-EVI13, and 2 of AML with t(1;22)(p13;q13);RBM15-MKL, 88 (19.6.7%) had AML with myelodysplasia-related changes (29 from morphological features of myelodysplasia and 59 from myelodysplasia-related cytogenetic abnormalities), 119 (26.6%) had AML, not otherwise categorized and 7(1.6%) had mixed phenotype acute leukemia (6 of T/myeloid and 1 of B/myeloid). [Discussion] Our comprehensive approach for diagnosis was a useful modality for precise diagnosis of uncertain cases, which might have been assigned to the category of AML, with not otherwise categorized, previously. As a result, the present study shows an increased prevalence of AML with recurrent genetic abnormalities or AML with myeloid dysplasia-related changes among pediatric patients with previously untreated AML. Analysis of the AML-05 trial will elucidate the prognostic impact of these categories. Disclosures: No relevant conflicts of interest to declare.

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EZH2 Mutations Are Associated with Low Blast Percentage in Bone Marrow and −7/Del(7q) Karyotype in De Novo Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v120.21.2544.2544 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2544-2544

Author(s):

Xiuli Wang ◽

Haiping Dai ◽

Qian WANG ◽

Qinrong Wang ◽

Yang Xu ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

De Novo ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Myelogenous Leukemia ◽

Prognostic Impact ◽

Coding Region ◽

Acute Myeloid

Abstract Abstract 2544 Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

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