RUNX3 Expression Is an Independent Prognostic Factor in Cytogenetically Abnormal Adult Acute Myeloid Leukemia (AML) Patients with Wild-Type FLT3.

Abstract 1662

RUNX3 is a member of Runt-related domain (RUNX) transcription factor family, which regulates cell proliferation and differentiation. Recent studies have suggested a role of RUNX3 in hematopoiesis. Our group previously showed that RUNX3 expression was repressed by fusion protein RUNX1-ETO and CBFβ-MYH11 in core-binding factor acute myeloid leukemia (CBF-AML) and had prognostic implication in childhood AML patients (Cheng et al, 2008). However, the prognostic value of RUNX3 in adult AML remains hitherto unaddressed. To investigate the prognostic value of RUNX3 expression in adult AML patients, we measured RUNX3 mRNA levels in the diagnostic bone marrow samples from 60 adult patients with de novo AML by real time quantitative PCR (RQ-PCR). Mutation status of KIT, FMS-like tyrosine kinase 3 (FLT3), nucleophosmin (NPM1) and CCAAT/enhancer-binding protein α (CEBPA) were assessed by direct sequencing. The adult AML patients (n=60) were dichotomized at median RUNX3 level and divided into high and low expression groups. There was no significant difference in age, sex, white blood cell (WBC) count, frequency of KIT, FLT3, NPM1 and CEBPA mutations between the two groups. Concordant with our previous observation, the low RUNX3 expression group was significantly associated with CBF-AML characterized by t(8;21) and inv(16) (p=0.002). However, in contrast to our previous findings in childhood AML, we observed significant association of survival with RUNX3 levels only when patients were stratified according to their cytogenetics and FLT3 mutation status but not when the whole patient cohort was analyzed or when the patients were stratified by age, sex, WBC count or other genetic aberrations (KIT, NPM1 or CEBPA mutation). In each cytogenetically normal and abnormal subgroup, AML patients were dichotomized at median RUNX3 into high and low expression groups. Among adult AML patients with abnormal karyotypes (n=36), high RUNX3 expression tended to have worse event-free survival (EFS) (high vs low= 50% vs 67%, p=0.213) and overall survival (OS) (61% vs 78%, p=0.233). Because potential relationship between FLT3 mutation status and RUNX3 expression was suggested in the study by Lacayo et al (2004), analysis was performed with further stratification according to the FLT3 status. Among cytogenetically abnormal patients with wild-type FLT3, high RUNX3 expression was significantly associated with poorer OS (53% vs 80%, p=0.048) and tended to have worse EFS (53% vs 73%, p=0.077). In multivariate analysis, RUNX3 expression was an independent prognostic factor for both EFS (p=0.026) and OS (p=0.021) along with age (p=0.013 and 0.004 respectively) and WBC count (p<0.0005 and 0.001 respectively) in this patient subgroup. The group of patients with mutant FLT3 was too small for analysis. In contrast to the finding in cytogenetically abnormal patients, there was a trend towards poorer EFS (high vs low = 50% vs 20%, p=0.066) and OS (50% vs 30%, p=0.118) for low RUNX3 expression in adult AML patients with a normal karyotype (n=20). However, no significant association was observed after stratification with FLT3 status. In conclusion, our findings suggested that unlike in childhood AML patients, the prognostic impact of RUNX3 in adult AML patients was dependent on cytogenetic status and that high RUNX3 expression was an independent adverse prognostic factor in cytogenetically abnormal adult AML patients with wild-type FLT3. A larger prospective study is currently underway to confirm the prognostic value of RUNX3 in adult AML.