Regulome analysis in B-acute lymphoblastic leukemia exposes Core Binding Factor addiction as a therapeutic vulnerability

Jason P. Wray, Elitza M. Deltcheva, Charlotta Boiers, Simon Richardson, Jyoti Bikram Chhetri, John Brown, Sladjana Gagrica, Yanping Guo, Anuradha Illendula, Joost H.A. Martens, Hendrik G. Stunnenberg, John H. Bushweller, Rachael Nimmo, Tariq Enver

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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 CBFβ results in cell death suggesting sustained requirement for RUNX1 activity which is recapitulated by chemical perturbation using an allosteric CBFβ-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 suggest that chemical intervention in the RUNX1 program may provide a therapeutic opportunity in ALL.

Originele taal-2Engels
Artikelnummer7124
TijdschriftNature Communications
Volume13
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - dec. 2022
Extern gepubliceerdJa

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