ONCOGENIC ROLE OF ARID5B IN THE MOLECULAR PATHOGENESIS OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Abstract

The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lymphoblastic leukemia (T-ALL) cells. However, critical factors downstream of the TAL1 complex have not been fully characterized. Here, we identified ARID5B as a collaborating factor involved in the transcriptional program in T-ALL. Using ChIP-seq and RNA-seq analysis for ARID5B, we discovered that ARID5B frequently co-occupies its target genes with TAL1 and co-ordinately controls their expression. Notably, ARID5B positively regulates expression of TAL1 and its regulatory partners. Additionally, we identified that ARID5B directly binds to the MYC enhancer and activates the expression of this oncogene. Transgenic study using zebrafish model indicated that forced expression of ARID5B in immature thymocytes results in thymus retention, radio-resistance and tumor formation in zebrafish. Taken together, our results indicate that ARID5B reinforces the TAL1-induced oncogenic transcriptional circuit and the MYC oncogene in T-ALL, thereby contributing to T-cell leukemogenesis.