RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia
Rashedul Islam,
Catherine E. Jenkins,
Qi Cao,
Jasper Wong,
Misha Bilenky,
Annaïck Carles,
Michelle Moksa,
Andrew P. Weng,
Martin Hirst
Affiliations
Rashedul Islam
Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada; Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada
Catherine E. Jenkins
Terry Fox Laboratory, BC Cancer, Vancouver, BC V5Z 1L3, Canada
Qi Cao
Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Jasper Wong
Genome Science and Technology Program, University of British Columbia, Vancouver, BC V6T 2B5, Canada
Misha Bilenky
Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada
Annaïck Carles
Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Michelle Moksa
Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
Andrew P. Weng
Terry Fox Laboratory, BC Cancer, Vancouver, BC V5Z 1L3, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada
Martin Hirst
Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada; Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada; Genome Science and Technology Program, University of British Columbia, Vancouver, BC V6T 2B5, Canada; Corresponding author
Summary: Runt-related transcription factor 1 (RUNX1) is oncogenic in diverse types of leukemia and epithelial cancers where its expression is associated with poor prognosis. Current models suggest that RUNX1 cooperates with other oncogenic factors (e.g., NOTCH1, TAL1) to drive the expression of proto-oncogenes in T cell acute lymphoblastic leukemia (T-ALL) but the molecular mechanisms controlled by RUNX1 and its cooperation with other factors remain unclear. Integrative chromatin and transcriptional analysis following inhibition of RUNX1 and NOTCH1 revealed a surprisingly widespread role of RUNX1 in the establishment of global H3K27ac levels and that RUNX1 is required by NOTCH1 for cooperative transcription activation of key NOTCH1 target genes including MYC, DTX1, HES4, IL7R, and NOTCH3. Super-enhancers were preferentially sensitive to RUNX1 knockdown and RUNX1-dependent super-enhancers were disrupted following the treatment of a pan-BET inhibitor, I-BET151.