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

Martinez-Soria, Natalia; McKenzie, Lynsey; Draper, Julia; Ptasinska, Anetta; Issa, Hasan; Potluri, Sandeep; Blair, Helen J.; Pickin, Anna; Isa, Asmida; Chin, Paulynn Suyin; Tirtakusuma, Ricky; Coleman, Daniel; Nakjang, Sirintra; Assi, Salam; Forster, Victoria; Reza, Mojgan; Law, Ed; Berry, Philip; Müller, Dorothee; Elder, Alex; Bomken, Simon N.; Pal, Deepali; Allan, James M.; Veal, Gareth J.; Cockerill, Peter N.; Wichmann, Christian; Vormoor, Josef; Lacaud, Georges; Bonifer, Constanze und Heidenreich, Olaf (2018): The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation. In: Cancer Cell, Bd. 34, Nr. 4: S. 626-642

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 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1535-6108
• Sprache: Englisch