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

Martinez-Soria, Natalia, McKenzie, Lynsey, Draper, Julia, Ptasinska, Anetta, Issa, Hasan, Potluri, Sandeep, Blair, Helen J., Pickin, Anna, Isa, Asmida, Chin, Paulynn Suyin, Tirtakusuma, Ricky, Coleman, Daniel, Nakjang, Sirintra, Assi, Salam, Forster, Victoria, Reza, Mojgan, Law, Ed, Berry, Philip, Mueller, Dorothee, Elder, Alex, Bomken, Simon N., Pal, Deepali, Allan, James M., Veal, Gareth J., Cockerill, Peter N., Wichmann, Christian, Vormoor, Josef, Lacaud, Georges, Bonifer, Constanze and Heidenreich, Olaf (2018) The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation. Cancer Cell, 34 (4). 626-642.e8. ISSN 1535-6108

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Abstract

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.

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