Cell cycle corruption in a preleukemic ETV6-RUNX1 model exposes RUNX1 addiction as a therapeutic target in acute lymphoblastic leukemia
Wray, J. P.; Deltcheva, E. M.; Boiers, C.; Richardson, S. E.; Chettri, J. B.; Gagrica, S.; Guo, Y.; Illendula, A.; Martens, J. H.; Stunnenberg, H. H.; Bushweller, J. H.; Nimmo, R.; Enver, T.
Show abstract
The ETV6-RUNX1 onco-fusion arises in utero, initiating a clinically silent pre-leukemic state associated with the development of pediatric B-acute lymphoblastic leukemia (B-ALL). We characterize the ETV6-RUNX1 regulome by integrating chromatin immunoprecipitation- and RNA-sequencing and show that ETV6-RUNX1 functions primarily through competition for RUNX1 binding sites and transcriptional repression. In pre-leukemia, this results in ETV6-RUNX1 antagonization of cell cycle regulation by RUNX1 as evidenced by mass cytometry analysis of B-lineage cells derived from ETV6-RUNX1 knock-in human pluripotent stem cells. In frank leukemia, knockdown of RUNX1 or its co-factor CBF{beta} results in cell death suggesting sustained requirement for RUNX1 activity which is recapitulated by chemical perturbation using an allosteric CBF{beta}-inhibitor. Strikingly, we show that RUNX1 addiction extends to other genetic subtypes of pediatric B-ALL and also adult disease. Importantly, inhibition of RUNX1 activity spares normal hematopoiesis. Our results implicate chemical intervention in the RUNX1 program as an exciting therapeutic opportunity in ALL.
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