Poor Outcome of RUNX1-Mutated (RUNX1-mut) Patients (Pts) with Primary, Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) and Associated Gene- and MicroRNA (miR) Expression Signatures,

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 1 st 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 1 st -line therapy and without alloSCT in CR1. This cohort comprised both younger [ 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 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 P =.003 in younger; P P RUNX1 -wt pts. In multivariable models, RUNX1 muts remained associated with lower CR rate ( P P P P 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 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. MiR s -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.