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The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation
Martinez-Soria, N McKenzie, L Draper, Julia E Ptasinska, A Issa, H Potluri, S Blair, HJ Pickin, A Isa, A Chin, PS
Martinez-Soria, N
McKenzie, L
Draper, Julia E
Ptasinska, A
Issa, H
Potluri, S
Blair, HJ
Pickin, A
Isa, A
Chin, PS
Citations
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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.
Authors
Martinez-Soria, N
McKenzie, L
Draper, Julia E
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, Georges
Bonifer, C
Heidenreich, O
McKenzie, L
Draper, Julia E
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, Georges
Bonifer, C
Heidenreich, O
Description
Date
2018
Publisher
Collections
Keywords
Type
Article
Citation
Martinez-Soria N, McKenzie L, Draper J, Ptasinska A, Issa H, Potluri S, et al. The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation. Cancer Cell [Internet]. 2018 Oct;34(4):626�642.e8.