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

Cancer Cell. 2018 Oct 8;34(4):626-642.e8. doi: 10.1016/j.ccell.2018.08.015.

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.

Keywords: CCND2; CDK6 inhibition; KIT mutation; RNAi screen; RUNX1/ETO; acute myeloid leukemia; cell-cycle control; fusion gene; imatinib; palbociclib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / genetics*
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 21 / genetics
  • Core Binding Factor Alpha 2 Subunit / genetics*
  • Cyclin D2 / genetics*
  • Gene Expression Regulation, Leukemic / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Male
  • Mice
  • Oncogene Proteins, Fusion / genetics
  • Oncogenes / genetics
  • Translocation, Genetic / genetics

Substances

  • CCND2 protein, human
  • Ccnd2 protein, mouse
  • Core Binding Factor Alpha 2 Subunit
  • Cyclin D2
  • Oncogene Proteins, Fusion
  • RUNX1 protein, human
  • Runx1 protein, mouse