The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation
Research output: Contribution to journal › Article › peer-review
Authors
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 language | English |
|---|---|
| Pages (from-to) | 626-642.e8 |
| Number of pages | 25 |
| Journal | Cancer Cell |
| Volume | 34 |
| Issue number | 4 |
| Publication status | Published - 8 Oct 2018 |
Keywords
- RNAi screen, fusion gene, cell-cycle control, CDK6 inhibition, RUNX1/ETO, CCND2, acute myeloid leukemia, palbociclib, KIT mutation, imatinib