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

Lookup NU author(s): Dr Lynsey McKenzie, Hasan Issa, Sandeep Potluri, Dr Helen Blair, Asmida Isa, Dr Ricky Tirtakusuma, Dan Coleman, Dr Sirintra Nakjang, Dr Victoria Forster, Dr Mojgan Reza, Dr Edward Law, Philip Berry, Dr Simon BomkenORCiD, Dr Deepali Pal, Professor James Allan, Professor Gareth Veal, Professor Olaf Heidenreich

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2018 The Author(s) 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. 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.

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Author(s): Martinez-Soria N, McKenzie L, Draper J, Ptasinska A, Issa H, Potluri S, Blair HJ, Pickin A, Isa A, Chin PS, Tirtakusuma R, Coleman D, Nakjang S, Assi S, Forster V, Reza M, Law E, Berry P, Mueller D, Elder A, Bomken SN, Pal D, Allan JM, Veal GJ, Cockerill PN, Wichmann C, Vormoor J, Lacaud G, Bonifer C, Heidenreich O

Publication type: Article

Publication status: Published

Journal: Cancer Cell

Year: 2018

Volume: 34

Issue: 4

Pages: 626-642.e8

Print publication date: 08/10/2018

Online publication date: 08/10/2018

Acceptance date: 02/04/2018

Date deposited: 09/10/2018

ISSN (print): 1535-6108

ISSN (electronic): 1878-3686

Publisher: Cell Press

URL: https://doi.org/10.1016/j.ccell.2018.08.015

DOI: 10.1016/j.ccell.2018.08.015

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