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ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis. (Genes Dev, Jan 2018)

Leong WZ1, Tan SH1, Ngoc PCT11, Amanda S1, Yam AWY1, Liau WS1, Gong Z2, Lawton LN1, Tenen DG1,3,4, Sanda T1,4.

Author information
1 Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore.
2 Department of Biological Sciences, National University of Singapore, 117543 Singapore.
3 Harvard Medical School, Boston, Massachusetts 02215, USA.
4 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore.

The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2-4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active transcription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. ARID5B positively regulates the expression of TAL1 and its regulatory partners. ARID5B also activates the expression of the oncogene MYC Importantly, ARID5B is required for the survival and growth of T-ALL cells, and forced expression of ARID5B in immature thymocytes results in thymus retention, differentiation arrest, radioresistance, and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the TAL1-induced regulatory circuit and MYC in T-ALL, thereby contributing to T-cell leukemogenesis.

KEYWORDS: ARID5B; MYC; T-cell acute lymphoblastic leukemia; TAL1; core regulatory circuit

PMID: 29326336