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

doi:10.1016/j.isci.2023.106795

RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia

iScience. 2023 May 3;26(6):106795. doi: 10.1016/j.isci.2023.106795. eCollection 2023 Jun 16.

Authors

Rashedul Islam^{1

2

3}, Catherine E Jenkins⁴, Qi Cao², Jasper Wong⁵, Misha Bilenky³, Annaïck Carles², Michelle Moksa², Andrew P Weng^{4

6}, Martin Hirst^{1

2

3

5}

Affiliations

¹ Bioinformatics Graduate Program, University of British Columbia, Vancouver, BC V5Z 4S6, Canada.
² Department of Microbiology and Immunology, Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
³ Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada.
⁴ Terry Fox Laboratory, BC Cancer, Vancouver, BC V5Z 1L3, Canada.
⁵ Genome Science and Technology Program, University of British Columbia, Vancouver, BC V6T 2B5, Canada.
⁶ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V6T 2B5, Canada.

Abstract

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.

Keywords: Cancer; Cancer systems biology; Molecular biology.