We are honored to welcome on Friday 17th of July at 11 AM, Caius Radu (Department of Molecular and Medical Pharmacology, UCLA) for a webinar entitled :
New immunometabolic checkpoints associated with PNP-mediated breakdown of guanine nucleosides
Loss of function mutations in purine nucleoside phosphorylase (PNP), a key gene in purine catabolism, trigger a severe immunodeficiency syndrome that preferentially impacts thymic T cell development, while B cell development is largely unaffected. Paradoxically, in a subset of patients PNP deficiency is also associated with autoimmunity. The selective effects of PNP deficiency on T cell development, the role of deoxycytidine kinase (dCK) in mediating these effects, and the increased susceptibility to autoimmunity associated with PNP loss of function mutations in humans are yet to be explained mechanistically. Using multiple in vitro and in vivo models, and leveraging a highly specific dCK inhibitor developed by our group (1-4) we have identified novel pleiotropic, multigenic-dependent and cell-context dependent consequences of restricting the breakdown of guanine nucleosides via PNP inhibition. Collectively, these findings indicate that PNP governs multiple metabolic checkpoints with distinct immune lineage-specific mechanisms and functions, and may guide the design of new therapeutic applications for currently available clinical stage PNP inhibitors.
References:
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- Le TM, Poddar S, Capri JR, Abt ER, Kim W, Wei L, Uong NT, Cheng CM, Braas D, Nikanjam M, Rix P, Merkurjev D, Zaretsky J, Kornblum HI, Ribas A, Herschman HR, Whitelegge J, Faull KF, Donahue TR, Czernin J, Radu CG. ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways. Nat Commun. 2017 Aug 14;8(1):241. PubMed Central PMCID: PMC5556071.