Adaptation of Acute Lymphoblastic Leukemia to the Central Nervous System and Peripheral Niches

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. In patients with ALL, preventative therapy delivered to the cerebrospinal fluid (CSF) is critical to prevent the spread of the disease. However, these CSF-directed treatments can become ineffective leading to relapse. CSF-directed therapy also increases the risk of long-term cognitive deficits. Novel therapies that target cancer-specific vulnerabilities while sparing healthy tissue can improve the quality of life of survivors. One unique feature of ALL cells is that they must be able to withstand diverse nutrient environments in humans, whether it be the nutrient-rich plasma or the relatively nutrient-poor CSF. However, whether adaptation to these various nutrient environments creates targetable metabolic dependencies remains unknown. In this thesis, we aim to characterize the molecular pathways that facilitate ALL survival in various physiological environments. Using an in vivo CRISPR screen, we demonstrate that copper metabolism is a targetable nutritional dependency in ALL. Copper depletion by either genetic deletion of the copper transporter or by dietary intervention significantly slowed the growth of both systemic and CNS leukemia. Furthermore, dietary copper depletion combined with the standard of care therapy methotrexate further inhibits progression in multiple models of ALL. Mechanistically, copper depletion compromises the proliferation of leukemia cells by inhibiting complex IV activity and nucleotide synthesis. In addition, we use multi-generational passaging of leukemia cells in mice to generate CNS and spleen-conditioned leukemia cells. We provide evidence that ADP-ribosylation may play an important role in in vivo leukemogenesis, potentially linking metabolism with post- translational modifications to drive metabolic adaptation. Overall, this work identifies novel metabolic vulnerabilities in ALL with the goal of identifying new therapeutic targets.