Tyrosine 625 plays a key role and cooperates with tyrosine 630 in MPL W515L-induced signaling and myeloproliferative neoplasms.
Tyrosine 625 plays a key role and cooperates with tyrosine 630 in MPL W515L-induced signaling and myeloproliferative neoplasms.
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酪氨酸 625 在 MPL W515L 诱导的信号传导和骨髓增殖性肿瘤中发挥关键作用并与酪氨酸 630 协同作用
DOI：
10.1186/s13578-016-0097-3
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发表时间：
2016
影响因子：
7.5
通讯作者：
Huang Z
中科院分区：
文献类型：
--
作者：
Yu C;Yang Q;Chen Y;Wang D;Levine R;Crispino J;Wen Q;Huang Z
骨髓增生性肿瘤（MPN）是一组促进骨髓中正常血细胞生成的血癌。伴随MPN发生的是干细胞的异常突变。研究表明MPL突变（MPL W515L或MPL W515K）与MPN患者有关。由于酪氨酸残基625和630介导正常的MPL信号传导，它们是否影响MPL w515l诱导的骨髓增生性肿瘤（mpn）尚不清楚。结果在本研究中，我们用MPL W515L（分别称为MPL515/625、MPL515/630和MPL515/625/630）中的苯丙氨酸替代它们中的一种或两种，进一步测试了它们在MPL W515L诱导的骨髓增生性肿瘤（mpn）中的功能。在体外，MPL515/630而不是MPL515/625或MPL515/625/630保留了诱导tpo独立增殖和增加集落形成单位巨核细胞（CFU-Mk）的能力。因此，我们观察到四个突变体对下游信号的不同激活，并且组成性地激活STAT5或AKT，而不是STAT3部分补偿MPL515/625/630的功能。进一步支持这一观点的是，stat5缺乏会损害MPL w515l诱导的CFU-Mk扩增。在体内，MPL515/630而不是MPL515/625或MPL515/625/630诱导的mpn的典型特征是白细胞和血小板计数高、脾肿大、肝肿大和骨髓细胞增多。令人惊讶的是，MPL515/625也引起骨髓细胞增多和脾肿大，但无其他显著特征。我们还观察到四种突变体对祖细胞、髓细胞和巨核细胞的不同影响。结论酪氨酸位点625和630在介导MPL w515l诱导的巨核细胞增殖和mpn中具有明显的特点。我们的研究还表明，MPL细胞质磷酸化的Y625和侧翼氨基酸可能成为mpn药物抑制的靶点。
BackgroundMyeloproliferative neoplasms (MPN) are a group of blood cancers that boost normal blood cell production in the bone marrow. Abnormal mutations in stem cells were found accompanying with the occurrence of MPN. It has been shown that MPL mutations (MPL W515L or MPL W515K) were involved in patients with MPN. Since tyrosine residues 625 and 630 mediate normal MPL signaling, whether them affect MPL W515L-induced myeloproliferative neoplasms (MPNs) is unknown.ResultsIn this study, we further tested their functions in MPL W515L-induced myeloproliferative neoplasms (MPNs) by substituting either or both of them with phenylalanine in MPL W515L (termed as MPL515/625, MPL515/630 and MPL515/625/630, respectively). In vitro, MPL515/630 but not MPL515/625 or MPL515/625/630 retained the ability to induce TPO-independent proliferation and increase colony-forming unit megakaryocytes (CFU-Mk). Accordingly, differential activation of the downstream signaling by four mutants was observed and constitutively active STAT5 or AKT instead of STAT3 partially compensated MPL515/625/630 function. Further support this, STAT5-deficiency impaired MPL W515L-induced CFU-Mk expansion. In vivo, MPL515/630 but not MPL515/625 or MPL515/625/630 induced typical features of MPNs with high WBC and platelet counts, splenomegaly, hepatomegaly and hypercellularity in the bone marrow. Surprisingly, MPL515/625 also caused hypercellularity of bone marrow and splenomegaly without any other significant features. We also observed differential effects of the four mutants on progenitors, myeloid cells and megakaryocytes.ConclusionsOur studies have revealed distinct features of tyrosine sites 625 and 630 in mediating MPL W515L-induced megakaryocyte hyperproliferation and MPNs. Our study also suggests that MPL cytosolic phosphorylated Y625 and flanking amino acids could become targets for pharmacologic inhibition in MPNs.