3065 – ETV6-RUNX1 ENHANCES THE SELF-RENEWAL OF HEMATOPOIETIC STEM CELLS AND CORRUPTS EARLY LYMPHOID DIFFERENTIATION

One-third of pediatric cancer patients are diagnosed with acute leukemia. Within this patient cohort, acute lymphoblastic leukemia (ALL) is by far the most predominant, accounting for ∼80% of the cases. Approximately 25% of B-cell ALL cases are caused by the ETV6-RUNX1 (TEL-AML1) translocation, a somatic translocation that emerges in utero. However, the ETV6-RUNX1 fusion gene is insufficient for leukemogenesis, and secondary events/hits are always required for transformation. Previous studies have proposed hematopoietic stem cells as potential targets for ETV6-RUNX1-associated ALL; however, an appropriate experimental model to answer this question definitively has been lacking. Here, we generated a mouse model in which ETV6-RUNX1 can be conditionally activated in any primary cell type of choice upon Tetracycline treatment. In line with previous studies, we observed an expansion of phenotypically defined HSCs and a block in B-cell differentiation upon ETV6-RUNX1 induction. With the benefits offered by our model, in which we can turn off the expression of ETV6-RUNX1, we were able to confirm that the candidate HSCs that expand in response to ETV6-RUNX1 are both phenotypically and functionally similar to normal HSCs. Moreover, when coupled with transheterozygous mutations in the Pax5 and Ebf1 genes, an established murine model system for B-ALL, ETV6-RUNX1 significantly accelerated B-ALL leukemia development. Through our ongoing work, we aim to unravel how ETV6-RUNX1 modulates gene expression to promote HSC expansion and leukemia development. It is our anticipation that these approaches will provide new insights on the biology that underlie the most common ALL translocation found in children.