Abstract 3336: ARID5B activates the TAL1-induced core regulatory circuit and the oncogene MYC, thereby promoting T-cell leukemogenesis

Abstract

Abstract The oncogenic transcription factor TAL1/SCL is abnormally expressed in 40-60% cases of T-cell acute lymphoblastic leukemia (T-ALL) cells. It induces an aberrant transcriptional program with its regulatory partners (E-proteins, LMO1/2, GATA3, RUNX1 and MYB) in malignant T cells. However, the critical factors that are directly activated by the TAL1 transcriptional complex and contribute to T-ALL pathogenesis are largely unknown. Here, we identified ARID5B, an AT-rich interactive domain (ARID) family DNA binding protein, as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. Our result indicated that ARID5B expression is downregulated at the CD4, CD8 double negative 2-4 stages in normal thymocytes, while it is activated by the TAL1 complex in human T-ALL cells. The enhancer located approximately 135 kb upstream of the ARID5B gene locus is associated with a super-enhancer in multiple T-ALL samples but not in normal thymus. These data suggested that ARID5B is aberrantly activated in T-ALL cells. Interestingly, ARID5B-bound regions are predominantly associated with active transcription, as shown by the active histone marks (H3K27ac, H3K4me1 and H3K4me3) by ChIP-seq analysis. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression. Notably, ARID5B positively regulates the expression of TAL1 and its regulatory partners (GATA3, RUNX1 and MYB). In addition, ARID5B activates the expression of the oncogene MYC. Importantly, ARID5B is required for the survival and growth of T-ALL cells in vitro, and forced expression of ARID5B in immature thymocytes results in thymus retention, radio-resistance and tumor formation in zebrafish. Our results indicate that ARID5B reinforces the oncogenic transcriptional program by positively regulating the core regulatory circuit and the oncogene MYC in T-ALL, thereby contributing to T-cell leukemogenesis. Citation Format: Wei Zhong Leong, Shi Hao Tan, Phuong Cao Thi Ngoc, Stella Amanda, Alice Wei Yee Yam, Wei-Siang Liau, Zhiyuan Gong, Lee N. Lawton, Daniel G. Tenen, Takaomi Sanda. ARID5B activates the TAL1-induced core regulatory circuit and the oncogene MYC, thereby promoting T-cell leukemogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3336.