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

Abstract

The oncogenic transcription factor 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 () as a collaborating oncogenic factor involved in the transcriptional program in T-ALL. 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 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 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 in T-ALL, thereby contributing to T-cell leukemogenesis.

Oncogenic transcriptional program driven by TAL1 in T-cell acute lymphoblastic leukemia

“…Therefore, ARID5B may serve as a transcriptional activator that enhances or consolidates the regulatory network initiated by the TAL1 complex. In addition, ARID5B overexpression in zebrafish leads to thymus retention, radio-resistance and differentiation arrest, some of which can result in T-ALL [95]. These results indicate that ARID5B plays critical oncogenic roles as a second-tier factor of TAL1 in T-ALL.…”

“…Several other transcriptional regulators have been implicated as TAL1 targets in T-ALL cells. Our group has recently performed a comprehensive analysis using RNAseqs after TAL1 knockdown and each of its regulatory partner proteins [95]. This analysis identified several highconfidence targets of TAL1, including ARID5B.…”

Zebrafish B cell acute lymphoblastic leukemia: new findings in an old model

“…myeloid leukemia (AML) and T-ALL [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. For T-ALL in particular, zebrafish models have been highly informative, advancing our understanding of T-ALL genetics, pro-and anti-oncogenic interactions between different genes and pathways, tumor heterogeneity, leukemia stem cells, and in screens for new therapeutics [28,[38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53]. However, despite the fact that zebrafish T-ALL models had proven to be fertile grounds for study, B-ALL modeling in D. rerio had not been fruitful, with only one low penetrance and long latency line reported [54].…”

TAL1 (1p32) deletion in lymphoid malignancies

“…Deregulation of TAL1 inhibits E-proteins heterodimerization leading to block of T-cell differentiation. However, the oncogenic role of TAL1 in T-cell transformation is more complex and is linked to their influence on the function of the core regulatory circuitry (Sanda T et al, 2012) as well as on multiple downstream targets including ARID5B, NKX3-1, MYCN, CDKN2A, ALDH1A2 and MIR223 (Leong WZ et al, 2017;Kusy S et al, 2010;Astolfi A et al, 2014;Hansson A et al, 2003;Ono Y et al, 1998;Mansour MR et al, 2013).…”