EXPLOITING CBF DEPENDENCY IN B-ACUTE LYMPHOBLASTIC LEUKAEMIA AS A NOVEL THERAPEUTIC APPROACH

Leukaemia is the most common childhood cancer and acute lymphoblastic leukaemia (ALL) is responsible for a third of all childhood cancer deaths. Despite the overall good prognosis, failure to eradicate the disease leads to relapse in ∼20% of patients and survival rates for infants are less than 50%. There is therefore a clear unmet need for less toxic and more effective targeted treatments. ETV6-RUNX1 translocation is the first-hit event in ∼25% of B-ALLs, initiating a clinically silent pre-leukaemia in utero. The translocation fuses almost the entire RUNX1 protein to the repressor domain of ETV6 and the chimeric product is proposed to mediate a block in B cell differentiation by repressing RUNX1 targets. Interestingly, the remaining RUNX1 allele is not mutated, but is instead often amplified suggesting an onco-supportive role of the endogenous RUNX1. Using genetic and pharmacological inhibition, we have discovered that RUNX1/CBF is essential for the growth and survival of B-ALL cells in vitro and in vivo. Global RNA-Seq on CBF-depleted B-ALL cells revealed significant downregulation of E2F and Myc signature genes along with a marked increase of p53 targets, consistent with these cells accumulating in G0 and subsequently becoming apoptotic. Notably, RNA-Seq and mass cytometry analyses of pro-B cells derived from an hiPSC ETV6-RUNX1 knockin model reveal a similar cell cycle trend indicating that ETV6-RUNX1-mediated inhibition of RUNX1 targets may induce a quiescence-like pre-leukaemic state while continued RUNX1 expression is essential for the survival of overt leukaemia. We propose that CBF-dependency is an Achilles heel of ALL cells that could be exploited by targeting either CBF itself or its key downstream nodes. By combining clinically tested compounds targeting multiple CBF effectors we aim to improve efficacy of potential treatments and circumvent resistance.