The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation

Research output: Contribution to journalArticle

Authors

  • Natalia Martinez-Soria
  • Lynsey McKenzie
  • Julia Draper
  • Hasan Issa
  • Sandeep Potluri
  • Helen J Blair
  • Asmida Isa
  • Ricky Tirtakusuma
  • Sirintra Nakjang
  • Victoria Forster
  • Mojgan Reza
  • Ed Law
  • Philip Berry
  • Dorothee Mueller
  • Alex Elder
  • Simon N Bomken
  • Deepali Pal
  • James M Allan
  • Gareth J Veal
  • Peter Cockerill
  • Christian Wichmann
  • Josef Vormoor
  • Georges Lacaud
  • Conny Bonifer
  • Olaf Heidenreich

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)626-642.e8
JournalCancer Cell
Volume34
Issue number4
Publication statusPublished - 8 Oct 2018