Epigenetic Alterations and Targeted Therapies in North American ATLL

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PROJECT SUMMARY/ABSTRACT Adult T-cell leukemia/lymphoma (ATLL) is a disease of malignant CD4+ T cells that develops in human T- lymphotropic virus-1 (HTLV-1) carriers. The 3-yr overall survival is an abysmal 25% even when managed with the most aggressive chemotherapy. No outcome-changing targeted treatment currently exists. Thus, improved understanding of pathogenesis and novel therapeutic strategies are urgently needed. We and others have shown that ATLLs diagnosed in the Japanese (J-ATLL) and North American (NA-ATLL) patients have very different clinical behavior, with the North American variant characterized by a higher rate of chemo-refractory disease and worse prognosis. Recently, we performed the first targeted exon sequencing analysis in 30 patients seen at our center and discovered significantly more mutations in genes controlling epigenetic modifications and fewer mutations in the TCR/NF-kappaB signaling pathways than the Japanese ATLLs. Strikingly, the frequency of EP300 mutations in our patient cohort (20%) was about 4 times that seen in the Japanese cohort (5.7%). One of the transcription factors that can be acetylated by p300 is BCL6, a transcription repressor that critically controls many functional aspects of mature B and T cells. We have discovered for the first time that BCL6 is expressed in primary ATLL samples and ATLL cell lines. Interestingly, NA-ATLL cell lines are notably more sensitive than J-ATLL cell lines to BCL6 inhibition. Additional experiments suggest that in NA-ATLL cells, BCL6 plays an essential role enabling survival of NA-ATLL cells as they cope with elevated DNA replication stress during S- phase of the cell cycle. Supporting the concept that the S-phase is an Achilles’ heel of NA-ATLL cells, these cells but not the J-ATLL cells are exquisitely sensitive to a PARP inhibitor, Olaparib. These findings support our working hypothesis that dysregulated epigenetic program is a central feature of NA-ATLL biology and that attenuated p300 activity combined with a unique role of BCL6 in S-phase programs provides a novel opportunity for therapeutic targeting. The following three specific aims are proposed to test this hypothesis. Aim 1. Elucidate the mechanisms by which p300 regulates chromatin and gene expression in NA-ATLL. Aim 2. Characterize the roles of p300 and BCL6 as regulators of DNA replication program and genome stability in NA-ATLL. Aim 3. Determine the mechanistic basis of PARPi sensitivity and design therapeutic strategies to target the S- phase vulnerabilities of NA-ATLL.