SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism.
SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism.
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DOI：
10.1038/s41419-020-03156-8
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发表时间：
2020-11-06
影响因子：
9
通讯作者：
Juszczynski P
中科院分区：
文献类型：
--
作者：
Polak A;Bialopiotrowicz E;Krzymieniewska B;Wozniak J;Stojak M;Cybulska M;Kaniuga E;Mikula M;Jablonska E;Gorniak P;Noyszewska-Kania M;Szydlowski M;Piechna K;Piwocka K;Bugajski L;Lech-Maranda E;Barankiewicz J;Kolkowska-Lesniak A;Patkowska E;Glodkowska-Mrowka E;Baran N;Juszczynski P
脾酪氨酸激酶 (SYK) 是一种重要的癌基因和信号传导介质，由细胞表面受体激活，对急性髓系白血病 (AML) 的维持和进展至关重要。 SYK 在 AML 细胞中的遗传或药理学抑制会导致分化增加、增殖减少和细胞凋亡。在此，我们讨论了 SYK 抑制对白血病干细胞 (LSC) 功能的影响，并评估了 AML 细胞生物学中 SYK 相关通路。使用功能获得性 MEK 激酶突变体和组成型活性 STAT5A，我们证明小分子 SYK 抑制剂 fostamatinib 的活性代谢物 R406 分别通过 MEK/ERK1/2 途径和 STAT5A 转录因子诱导分化并阻断 AML 细胞的克隆形成潜力。用 R406 对 SYK 进行药理抑制可减少体外定义为 CD34+CD38−CD123+ 和 CD34+CD38−CD25+ 的 LSC 区室，并降低由低丰度活性氧确定的 LSC 的活力。当异种移植到免疫缺陷 NSG/J 小鼠时，用 R406 离体处理的原代白血病细胞表现出较低的植入潜力。从机制上讲，这些效应是由 LSC 中线粒体生物发生紊乱和氧化代谢 (OXPHOS) 抑制介导的。这些机制似乎部分依赖于 STAT5 及其靶基因 MYC 的抑制，MYC 是一种明确的线粒体生物发生诱导剂。此外，抑制 SYK 会增加 LSC 对阿糖胞苷 (AraC) 的敏感性，阿糖胞苷是 AML 诱导治疗的标准。总而言之，我们的研究结果表明，SYK 促进 OXPHOS 并以至少部分涉及 STAT5 的机制参与 AML LSC 的代谢重编程，并且 SYK 抑制作用针对 AML 中的 LSC。由于活性 SYK 在大多数 AML 患者中表达并且预后较差，因此 SYK 抑制剂与标准化疗药物（如 AraC）的组合构成了一种新的治疗方式，应在未来的临床试验中进行评估。
Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38−CD123+ and CD34+CD38−CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials.
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影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
DOI：
10.1016/j.bbrc.2010.10.112
发表时间：
2010-11-26
影响因子：
3.1
作者：
Chueh FY;Leong KF;Yu CL
通讯作者：
Yu CL
影响因子：
4.8
作者：
Ariyoshi, K;Nosaka, T;Kitamura, T
通讯作者：
Kitamura, T
影响因子：
--
作者：
Choi, HS;Kim, JW;Kim, C
通讯作者：
Kim, C