The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation

Natalia Martinez-Soria, Lynsey McKenzie, Julia Draper, Anetta Ptasinska, Hasan Issa, Sandeep Potluri, Helen J Blair, Anna Pickin, Asmida Isa, Paulynn Suyin Chin, Ricky Tirtakusuma, Daniel Coleman, Sirintra Nakjang, Salam Assi, Victoria Forster, Mojgan Reza, Ed Law, Philip Berry, Dorothee Mueller, Cameron OsborneAlex Elder, Simon N Bomken, Deepali Pal, James M Allan, Gareth J Veal, Peter N Cockerill, Christian Wichmann, Josef Vormoor, Georges Lacaud, Constanze Bonifer, Olaf Heidenreich

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

Oncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.

Originele taal-2Engels
Pagina's (van-tot)626-642.e8
TijdschriftCancer cell
Volume34
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 8 okt. 2018
Extern gepubliceerdJa

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