OVERCOMING ADULT T-CELL LEUKEMIA/LYMPHOMA SURVIVAL PATHWAYS WITH mTORC1 BLOCKADE and BH3-MIMETICS

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy caused by infection with human T-lymphotropic virus type 1 (HTLV-1). ATLL remains incurable for most patients due to therapy resistance and complex molecular pathology. This thesis examines how mTORC1 signaling, epigenetic reprogramming, and apoptotic regulation sustain the survival and drug resistance of ATLL cells. Using a panel of ATLL-derived and HTLV-1-transformed cell lines, we observed that mTORC1 inhibition with Everolimus significantly induced cell death, marked by accumulation of reactive oxygen species (ROS) and de-repression of miR-31-5p, a negative regulator of the non-canonical NF-ĸB pathway. The effect on miR-31-5p expression was attributed to Everolimus-induced downregulation of EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which is known to play a key role in epigenetic silencing of the microRNA in ATLL cells. Profiling of BCL-2 family proteins revealed that ATLL cells depend on anti-apoptotic members (primarily BCL-xL, MCL1, and BCL-2) for survival. Selective targeting of these proteins with BH3-mimetic drugs induced cell death, and combining Everolimus with BH3 mimetics produced greater cell death than either treatment alone. These observations support a model in which mTORC1 inhibition primes the mitochondrial apoptotic pathway in part through de-repression of miR-31, which leads to loss of survival signals sustained by NF-ĸB (including BCL-xL), so that BH3 mimetics can more effectively trigger cell death. Our results provide new insight into the survival mechanisms in ATLL cells and suggest that co-targeting aberrant mTORC1/epigenetic signaling and apoptotic defenses could improve therapeutic outcomes for this devastating disease.