Abstract
Ikaros encodes a transcription factor that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which Ikaros regulates gene expression and cellular proliferation in T-ALL are unknown. Re-introduction of Ikaros into Ikaros-null T-ALL cells resulted in cessation of cellular proliferation and induction of T-cell differentiation. We performed dynamic, global, epigenomic, and gene expression analyses to determine the mechanisms of Ikaros tumor suppressor activity. Our results identified novel Ikaros functions in the epigenetic regulation of gene expression: Ikaros directly regulates de novo formation and depletion of enhancers, de novo formation of active enhancers and activation of poised enhancers; Ikaros directly induces the formation of super-enhancers; and Ikaros demonstrates pioneering activity by directly regulating chromatin accessibility. Dynamic analyses demonstrate the long-lasting effects of Ikaros DNA binding on enhancer activation, de novo formation of enhancers and super-enhancers, and chromatin accessibility. Our results establish that Ikaros’ tumor suppressor function occurs via global regulation of the enhancer and super-enhancer landscape and through pioneering activity. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and Ikaros-induced enhancers, and that are responsible for the cessation of proliferation and induction of T-cell differentiation in T-ALL cells.
Original language | English (US) |
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Pages (from-to) | 2720-2731 |
Number of pages | 12 |
Journal | Leukemia |
Volume | 33 |
Issue number | 11 |
DOIs | |
State | Published - Nov 1 2019 |
Funding
Acknowledgements This work was supported by R01CA209829 (KJP and SD); R01CA213912 (SD and CS) F30CA221109 (JLP); R01DK110108 and R01CA204044 (SH); R35GM124820 and R01HG009906 (FY); the PhRMA foundation (BZ); a Hyundai Hope on Wheels Scholar Grant, and the Four Diamonds Fund of the Pennsylvania State University College of Medicine (to SD and CS); Bear Necessities Pediatric Cancer Foundation, Alex’s Lemonade Stand Foundation, and the John Wawrynovic Leukemia Research Scholar Endowment (to SD); and the St. Baldrick’s Foundation and Bear Necessities (CG).
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research