SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells.
SUMOylation disassembles the tetrameric pyruvate kinase M2 to block myeloid differentiation of leukemia cells.
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SUMOylation 分解四聚体丙酮酸激酶 M2 以阻止白血病细胞的骨髓分化
DOI：
10.1038/s41419-021-03400-9
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发表时间：
2021-01-20
影响因子：
9
通讯作者：
Lu Y
中科院分区：
文献类型：
--
作者：
Xia L;Jiang Y;Zhang XH;Wang XR;Wei R;Qin K;Lu Y
白血病是由于造血祖细胞在不同阶段的分化/成熟被阻断而导致白血病细胞不受控制地增殖。然而，阻止细胞分化的信号通路仍不清楚。在此，我们发现，SUMO化的M2亚型的丙酮酸激酶（PKM 2），一种限速糖酵解酶催化磷酸烯醇丙酮酸去磷酸化丙酮酸，是普遍存在于各种白血病细胞系，以及原发性样品白血病患者通过多反应监测为基础的靶向质谱分析。PKM 2赖氨酸270（K270）的SUMO化引发PKM 2的构象从四聚体变为二聚体，降低PK活性，并导致PKM 2的核转位。PKM 2的SUMO 1修饰通过SUMO相互作用基序募集并促进RUNX 1的降解，导致NB 4和U937白血病细胞的髓样分化阻断。用SUMO化缺陷突变体（K270 R）替换野生型PKM 2消除了与RUNX 1的相互作用，并且在体外和异种移植模型中阻断了骨髓分化。我们的研究结果表明PKM 2是白血病细胞分化的重要调节因子，是一个潜在的治疗靶点，可能与分化治疗在白血病治疗中发挥协同作用。
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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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
Adenanthin 靶向过氧化还原蛋白 I 和 II 诱导白血病细胞分化
影响因子：
14.8
作者：
Liu, Chuan-Xu;Yin, Qian-Qian;Chen, Guo-Qiang
通讯作者：
Chen, Guo-Qiang
丙酮酸激酶M2激活剂促进四聚体形成并抑制肿瘤发生。
影响因子：
14.8
作者：
Anastasiou, Dimitrios;Yu, Yimin;Israelsen, William J.;Jiang, Jian-Kang;Boxer, Matthew B.;Hong, Bum Soo;Tempel, Wolfram;Dimov, Svetoslav;Shen, Min;Jha, Abhishek;Yang, Hua;Mattaini, Katherine R.;Metallo, Christian M.;Fiske, Brian P.;Courtney, Kevin D.;Malstrom, Scott;Khan, Tahsin M.;Kung, Charles;Skoumbourdis, Amanda P.;Veith, Henrike;Southall, Noel;Walsh, Martin J.;Brimacombe, Kyle R.;Leister, William;Lunt, Sophia Y.;Johnson, Zachary R.;Yen, Katharine E.;Kunii, Kaiko;Davidson, Shawn M.;Christofk, Heather R.;Austin, Christopher P.;Inglese, James;Harris, Marian H.;Asara, John M.;Stephanopoulos, Gregory;Salituro, Francesco G.;Jin, Shengfang;Dang, Lenny;Auld, Douglas S.;Park, Hee-Won;Cantley, Lewis C.;Thomas, Craig J.;Heiden, Matthew G. Vander
通讯作者：
Heiden, Matthew G. Vander
影响因子：
21.3
作者：
Liu F;Ma F;Wang Y;Hao L;Zeng H;Jia C;Wang Y;Liu P;Ong IM;Li B;Chen G;Jiang J;Gong S;Li L;Xu W
通讯作者：
Xu W
DOI：
10.1126/science.1212728
发表时间：
2012-01-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kessler JD;Kahle KT;Sun T;Meerbrey KL;Schlabach MR;Schmitt EM;Skinner SO;Xu Q;Li MZ;Hartman ZC;Rao M;Yu P;Dominguez-Vidana R;Liang AC;Solimini NL;Bernardi RJ;Yu B;Hsu T;Golding I;Luo J;Osborne CK;Creighton CJ;Hilsenbeck SG;Schiff R;Shaw CA;Elledge SJ;Westbrook TF
通讯作者：
Westbrook TF