SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells
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 is...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03400-9 |
| _version_ | 1818456734748901376 |
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| author | Li Xia Yue Jiang Xue-Hong Zhang Xin-Ran Wang Ran Wei Kang Qin Ying Lu |
| author_facet | Li Xia Yue Jiang Xue-Hong Zhang Xin-Ran Wang Ran Wei Kang Qin Ying Lu |
| author_sort | Li Xia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T22:31:23Z |
| format | Article |
| id | doaj.art-c4447d792220453bb13066aec5d92013 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-14T22:31:23Z |
| publishDate | 2021-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-c4447d792220453bb13066aec5d920132022-12-21T22:45:14ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111310.1038/s41419-021-03400-9SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cellsLi Xia0Yue Jiang1Xue-Hong Zhang2Xin-Ran Wang3Ran Wei4Kang Qin5Ying Lu6Institute 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 Jiao Tong University School of MedicineDepartment of Hematology, Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, The Second Hospital of Dalian Medical UniversityDepartment of Hematology, Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, The Second Hospital of Dalian Medical UniversityInstitute 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 Jiao Tong University School of MedicineInstitute 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 Jiao Tong University School of MedicineInstitute 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 Jiao Tong University School of MedicineInstitute 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 Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1038/s41419-021-03400-9 |
| spellingShingle | Li Xia Yue Jiang Xue-Hong Zhang Xin-Ran Wang Ran Wei Kang Qin Ying Lu SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells Cell Death and Disease |
| title | SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells |
| title_full | SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells |
| title_fullStr | SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells |
| title_full_unstemmed | SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells |
| title_short | SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells |
| title_sort | sumoylation disassembles the tetrameric pyruvate kinase m2 to block myeloid differentiation of leukemia cells |
| url | https://doi.org/10.1038/s41419-021-03400-9 |
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