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Abstract
Leukemia arises from blockage of the differentiation/maturation of hematopoietic progenitor cells at different stages with uncontrolled proliferation of leukemic cells. However, the signal pathways that block cell differentiation remain unclear. Herein we found that SUMOylation of the M2 isoform of pyruvate kinase (PKM2), a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, is prevalent in a variety of leukemic cell lines as well as primary samples from patients with leukemia through multiple-reaction monitoring based targeted mass spectrometry analysis. SUMOylation of PKM2 lysine 270 (K270) triggered conformation change from tetrameric to dimeric of PKM2, reduced PK activity, and led to nuclear translocation of PKM2. SUMO1 modification of PKM2 recruits and promotes degradation of RUNX1 via a SUMO-interacting motif, resulting in blockage of myeloid differentiation of NB4 and U937 leukemia cells. Replacement of wild type PKM2 with a SUMOylation-deficient mutant (K270R) abrogated the interaction with RUNX1, and the blockage of myeloid differentiation in vitro and in xenograft model. Our results establish PKM2 as an essential modulator of leukemia cell differentiation and a potential therapeutic target, which may offer synergistic effect with differentiation therapy in the treatment of leukemia.
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1 Shanghai Jiao Tong University School of Medicine, Institute of Dermatology, Xinhua Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education and Department of Core Facility of Basic Medical Sciences, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
2 The Second Hospital of Dalian Medical University, Department of Hematology, Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Dalian, China (GRID:grid.452828.1)
3 Shanghai Jiao Tong University School of Medicine, Institute of Dermatology, Xinhua Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education and Department of Core Facility of Basic Medical Sciences, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293); The Second Hospital of Dalian Medical University, Department of Hematology, Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Dalian, China (GRID:grid.452828.1)