Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3.
Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3.
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DOI：
10.1038/leu.2016.289
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发表时间：
2017-04
期刊：
影响因子：
11.4
通讯作者：
Frampton J
中科院分区：
文献类型：
--
作者：
Clarke M;Volpe G;Sheriff L;Walton D;Ward C;Wei W;Dumon S;García P;Frampton J
骨髓增生性肿瘤（MPN），在骨髓中产生过多的血细胞，最近已与基因决定的MYB转录因子表达减少。在这里，我们使用小鼠MYB敲低模型与MPN样表型，以显示如何较低水平的MYB导致骨髓祖细胞的干细胞特性。改变的祖细胞特性的特征是升高的细胞因子反应性，特别是对IL-3的反应性，这是由于受体表达增加和MAPK活性增加导致蛋白质合成的关键调节因子核糖体蛋白S6的磷酸化增强。MYB通过直接调节编码负调节因子SPRY 2的基因的转录而作用于MAPK信号传导。这种机制的见解指出，可能是针对治疗MPN的途径。
Myeloproliferative neoplasms (MPN), which overproduce blood cells in the bone marrow, have recently been linked with a genetically determined decrease in expression of the MYB transcription factor. Here, we use a mouse MYB knockdown model with an MPN-like phenotype to show how lower levels of MYB lead to stem cell characteristics in myeloid progenitors. The altered progenitor properties feature elevated cytokine responsiveness, especially to IL-3, which results from increased receptor expression and increased MAPK activity leading to enhanced phosphorylation of a key regulator of protein synthesis, ribosomal protein S6. MYB acts on MAPK signaling by directly regulating transcription of the gene encoding the negative modulator SPRY2. This mechanistic insight points to pathways that might be targeted therapeutically in MPN.