In:
Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3454-3454
Abstract:
Abstract 3454 RUNX1 encodes the α subunit of core binding factor, a heterodimeric transcription factor required for normal hematopoiesis. Acquired RUNX1 mutations (muts) have been associated with poor clinical outcome in AML; however, prior studies analyzed pts heterogeneous for cytogenetics, age, AML type (primary or secondary), and treatment received [including allogeneic stem cell transplant (alloSCT) in 1st complete remission (CR1)] and contained limited data regarding the potential molecular drivers of the worse outcome. We report a relatively large study testing the prognostic impact of RUNX1 muts in primary CN-AML pts (n=392) treated similarly with intensive cytarabine/anthracycline-based 1st-line therapy and without alloSCT in CR1. This cohort comprised both younger [ 〈 60 years (y); n=173] and older (≥60 y; n=219) pts. Pretreatment marrow (n=303) and blood (n=89) were analyzed centrally for RUNX1 muts by PCR and direct sequencing, and for FLT3-ITD, FLT3-TKD, MLL-PTD and NPM1, CEBPA, WT1, IDH1, IDH2 and TET2 muts. Gene and miR expression profiles were derived using microarrays. RUNX1 muts were found in 12.5% of pts (8% younger, 16% older), and were associated with lower hemoglobin (P=.01), white blood cells (WBC; P=.04), and blood blasts (P=.006). RUNX1-mut pts harbored NPM1 (P 〈 .001) and CEBPA muts (P=.06) less frequently than RUNX1-wild-type (RUNX1-wt) pts. RUNX1-mut pts had lower CR rates (P=.005 in younger; P=.006 in older), and shorter disease-free (DFS; P=.058 in younger; P 〈 .001 in older), overall (OS; P=.003 in younger; P 〈 .001 in older) and event-free (EFS; P 〈 .001 for younger and older; Figures 1 and 2) survival than RUNX1-wt pts. In multivariable models, RUNX1 muts remained associated with lower CR rate (P 〈 .001) and shorter DFS (P 〈 .001), OS (P 〈 .001), and EFS (P 〈 .001; Table) after adjustment for clinical and molecular variables.Figure 1.Figure 1. Figure 2.Figure 2. Table 1Multivariable analysis for EFS according to RUNX1-mut status in all CN-AML ptsHREFSPRUNX1, mut v wt2.271.65–3.12 〈 .001FLT3-ITD, ITD v no ITD1.571.27–1.95 〈 .001WT1, mut v wt1.441.02–2.01.04WBC, continuous 50 unit increase1.131.04–1.23.006Age group, ≥60y v 〈 60y1.801.46–2.22 〈 .001Note: A hazard ratio (HR) 〉 1 corresponds to a higher risk for higher values of continuous variables and the 1st level listed of a dichotomous variable. To gain biological insight, RUNX1 mut-associated gene and miR expression signatures were derived in CN-AML for the first time. Older, NPM1-wt pts were analyzed since RUNX1 muts are more common in this age group and are nearly exclusive from NPM1 muts, which have their own characteristic gene-expression signature. This yielded 484 probe sets representing 278 named genes differentially expressed between RUNX1-mut (n=31) and RUNX1-wt (n=45) pts (P 〈 .001). Genes normally expressed in hematopoietic stem (HSC) and early progenitor cells, including DNTT, BAALC, MN-1, CD109, P2RY14, FOXO1 and FLT-3 were upregulated in RUNX1-mut pts, as were components of the Wnt-signaling pathway, LRP6 and TCF4, that promote self-renewal and proliferation of HSCs. Genes upregulated (SETBP1, RBPMS, and SLC37A3) and downregulated (CCNA1 and RNASE3) in AML stem cells relative to AML progenitors were similarly deregulated in the RUNX1-mut signature. B cell lineage genes BLNK, IGHM, IRF8 and several class II MHC molecules were upregulated in RUNX1-mut pts while CEBPA, a key promoter of granulopoiesis, was downregulated. Genes implicated in chemoresistance, GAS6, PRKCE, and PTK2, were upregulated and MYCN, a promoter of both proliferation and apoptosis of myeloid cells, was downregulated in RUNX1-mut pts. Seven miRs were differentially expressed between RUNX1-mut and RUNX1-wt pts. Two members of the let-7 tumor suppressor family, which represses self-renewal and promotes differentiation of stem cells, were downregulated, as was miR-223, a positive regulator of granulopoiesis. MiRs -99a and -100 were also downregulated and miRs -211 and -595 upregulated in association with RUNX1 muts. In summary, RUNX1 muts are twice as common in older CN-AML pts than younger. They negatively impact on outcome in both younger and older pts not receiving alloSCT in CR1. RUNX1-mut blasts have molecular features of normal/malignant stem cells and B cells, which may explain their chemoresistance and guide novel therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V118.21.3454.3454
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2011
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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