RUNX1A isoform is overexpressed in acute myeloid leukemia and is associated with FLT3 internal tandem duplications

Background. RUNX1A is the shortest and least expressed of the RUNX1 three main isoforms (A, B, C); despite this, the leukemogenic role of its overexpression has been clearly described. Several studies have shown RUNX1A involvement in different blood cancers and pilot observations in acute leukemia have been reported. Methods. In this context, we evaluated RUNX1 isoformsexpression in a cohort of acute myeloid leukemia (AML) patients and associated our data with significant AML clinical and biological parameters. A focus was performed on FLT3 mutated cases. Genome-wide methylation data from the TF-1 cell line were studied to investigate the possible role of epigenetic regulation in RUNX1 expression. To verify whether RUNX1A upregulation is linked to a specific transcriptional profile, high-throughput RNA sequencing was conducted. Results. At diagnosis, we found RUNX1A and RUNX1B overexpression , with higher median levels in thrombocytopenic cases. No difference was observed for RUNX1C . RUNX1A overexpression is higher in more immature AML phenotypes. According to the mutational profile, FLT3 internal tandem duplication (ITD) positive cases have the highest RUNX1A levels and the presence of FLT3 -ITD was the only molecular variable able to influence RUNX1A expression. RUNX1A overexpression is disease-related, associated with a specific transcriptional profile, and reappears at relapse, with no clear kinetics except in FLT3 -ITD cases. Conclusions. Overall, we demonstrate RUNX1A overexpression in AML and its association with the FLT3 -ITD molecular subtype. Our data shed light on the dark side of RUNX1 deregulation, paving the way for further investigations.