Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors
Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors
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DOI：
10.1182/blood-2006-05-023093
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发表时间：
2006-12-15
期刊：
影响因子：
20.3
通讯作者：
Verma, Amit
中科院分区：
文献类型：
--
作者：
Navas, Tony A.;Mohindru, Mani;Verma, Amit
骨髓增生异常综合征 (MDS) 是一组异质性血液疾病，其特征是无效造血导致的难治性细胞减少。对任何统一致病途径的了解有限，阻碍了有效治疗方法的发展。我们提供的证据表明 p38 MAP 激酶在 MDS 骨髓中被组成型激活或磷酸化。这种激活在低风险MDS的各种形态亚型中均观察到，并且与MDS造血祖细胞中观察到的细胞凋亡增强相关。最重要的是，新型小分子抑制剂 SCIO-469 对 p38 α 的药理学抑制可减少 MDS CD34(+) 祖细胞的凋亡，并导致红细胞和骨髓集落形成呈剂量依赖性增加。 siRNA 对主要 p38 α 同工型的下调也会导致体外 MDS 骨髓祖细胞的造血能力增强。这些数据表明 p38 MAPK 与低风险 MDS 无效造血的病理学有关，并为 SCIO-469 在 MDS 中的临床研究提供了强有力的理论依据。 （血液。2006 年；108：4170-4177）(c) 2006 年，美国血液学会。
The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenlas as a result of ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated or phosphorylated in MDS bone marrows. Such activation is uniformly observed in varied morphologic subtypes of low-risk MDS and correlates with enhanced apoptosis observed in MDS hematopoietic progenitors. Most importantly, pharmacologic inhibition of p38 alpha by a novel small molecule inhibitor, SCIO-469, decreases apoptosis in MDS CD34(+) progenitors and leads to dose-dependant increases in erythroid and myeloid colony formation. Down-regulation of the dominant p38 alpha isoform by siRNA also leads to enhancement of hematopolesis in MDS bone marrow progenitors in vitro. These data implicate p38 MAPK in the pathobiology of ineffective hematopoiesis in low-risk MDS and provide a strong rationale for clinical investigation of SCIO-469 in MDS. (Blood. 2006;108:4170-4177)(c) 2006 by The American Society of Hematology.