The role of pyruvate kinase as a therapeutic target in T-ALL

ABSTRACT T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that occurs primarily in children but can also occur in adults. Despite recent advances in treatments, 20-50% of patients do show primary resistance or relapse after treatment and ultimately die from their disease, highlighting the need to discover novel targeted therapeutic approaches. The detection of highly prevalent NOTCH1 activating mutations in T-ALL, seen in ~60% of patients, led to the discovery of NOTCH1 signaling inhibitors such as gamma-secretase inhibitors (GSIs), that block a critical proteolytical cleavage step required for NOTCH1 maturation and activation. GSIs are currently being explored in clinical trials for relapsed/refractory cases, however, the responses observed as a single agent treatment have been generally limited, such that the identification of novel targets and combination therapies capable of delivering strong and synergistic antileukemic responses in patients is one of the most urgent goals in the T-ALL field. Our lab has previously demonstrated the therapeutic benefit of targeting metabolic routes in T-ALL. In this context, my preliminary results strongly suggest that targeting the glycolytic enzyme pyruvate kinase (PKM) has strong antileukemic effects on its own, and significantly synergizes with GSI treatment in vivo. Still, the role of PKM in T- ALL remains largely unknown. Notably, PKM has two different isoforms, PKM1 and PKM2, and we have already generated conditional knockout leukemias for each specific isoform, as well as for both of them concomitantly, which will allow us to exquisitely analyze the effects of pyruvate kinase in leukemia progression and response to therapy in vivo. Thus, the aim of this project is to mechanistically dissect the function of PKM in T-ALL by using a combination of gene expression, metabolomic profiling, epigenetic profiling and experimental therapeutics in vivo, taking advantage of our unique genetic tools. Our results will shed light on the mechanisms by which NOTCH1 controls cancer cell metabolism and will reveal PKM as a putative novel target for the treatment of T-ALL.