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

• Published in: Cancer cell Vol. 34; no. 4; pp. 626 - 642.e8
• Main Authors: 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, Osborne, Cameron, Elder, Alex, Bomken, Simon N., Pal, Deepali, Allan, James M., Veal, Gareth J., Cockerill, Peter N., Wichmann, Christian, Vormoor, Josef, Lacaud, Georges, Bonifer, Constanze, Heidenreich, Olaf
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.10.2018; Cell Press
• Subjects: acute myeloid leukemia; Animals; CCND2; CDK6 inhibition; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; cell-cycle control; Chromosomes, Human, Pair 21 - genetics; Core Binding Factor Alpha 2 Subunit - genetics; Cyclin D2 - genetics; fusion gene; Gene Expression Regulation, Leukemic - genetics; Humans; imatinib; KIT mutation; Leukemia, Myeloid, Acute - genetics; Male; Mice; Oncogene Proteins, Fusion - genetics; Oncogenes - genetics; palbociclib; RNAi screen; RUNX1/ETO; Translocation, Genetic - genetics; RNAi screen; KIT mutation; CCND2; fusion gene; CDK6 inhibition; acute myeloid leukemia; imatinib; cell-cycle control; RUNX1/ETO; palbociclib
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2018.08.015

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. [Display omitted] •An RNAi screen identifies CCND2 as a crucial transcriptional target of RUNX1/ETO•RUNX1/ETO promotes CCND2 expression by binding to an upstream element•CCND2 knockdown inhibits RUNX1/ETO-driven leukemic expansion in vitro and in vivo•RUNX1/ETO-expressing leukemic cells are highly sensitive to a CDK4/6 inhibitor Using in vitro and in vivo screens to identify essential RUNX1/ETO transcriptional targets in AML, Martinez-Soria identify CCND2 as required for leukemia maintenance and self-renewal. Targeting this dependency using the CDK4/6 inhibitor palbociclib prolongs the survival of AML PDX models.