ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis

作者：Leong Wei Zhong; Tan Shi Hao; Phuong Cao Thi Ngoc; Amanda Stella; Yam Alice Wei Yee; Liau Wei Siang; Gong Zhiyuan; Lawton Lee N; Tenen Daniel G; Sanda Takaomi

来源：Genes & Development, 2017, 31(23-24): 2343-2360.

DOI：10.1101/gad.302646.117

<jats:p>The oncogenic transcription factor <jats:italic>TAL1/SCL</jats:italic> 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 <jats:italic>AT-rich interactive domain 5B</jats:italic> (<jats:italic>ARID5B</jats:italic>) as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. <jats:italic>ARID5B</jats:italic> 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 <jats:italic>ARID5B</jats:italic> 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 <jats:italic>MYC</jats:italic>. Importantly, ARID5B is required for the survival and growth of T-ALL cells<jats:italic>,</jats:italic> 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 <jats:italic>MYC</jats:italic> in T-ALL, thereby contributing to T-cell leukemogenesis.</jats:p>

• 出版日期2017-12-1