Journal
CANCER CELL
Volume 34, Issue 4, Pages 626-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.08.015
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Funding
- North of England Children's Cancer Research Fund [12055, 15005, 17-245]
- University Sains Malaysia PhD studentship
- Children's Cancer and Leukaemia Group grant
- CRUK program [C27943/A12788]
- Bloodwise [15001]
- MRC/Leuka Clinical Training Fellowship
- Wellcome Trust [087961]
- MRC [MR/M009157/1, MR/P019609/1] Funding Source: UKRI
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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 epi-genomic 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.
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