Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase.
Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase.
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DOI：
10.1158/0008-5472.can-10-2933
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Verma A
中科院分区：
文献类型：
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作者：
Zhou L;McMahon C;Bhagat T;Alencar C;Yu Y;Fazzari M;Sohal D;Heuck C;Gundabolu K;Ng C;Mo Y;Shen W;Wickrema A;Kong G;Friedman E;Sokol L;Mantzaris I;Pellagatti A;Boultwood J;Platanias LC;Steidl U;Yan L;Yingling JM;Lahn MM;List A;Bitzer M;Verma A
尽管骨髓增生异常综合征的特征是无效的造血，但导致骨髓衰竭的分子改变尚未得到很好的阐明。我们先前已经表明骨髓抑制性TGF-β途径在MDS祖细胞中被组成性激活。由于关于MDS中细胞外TGF-β水平上调的数据相互矛盾，我们希望确定这种疾病中TGF-β途径过度活化和随后的造血抑制的分子基础。我们在MDS骨髓来源的CD 34+细胞的基因表达研究的大型荟萃分析中观察到，TGF-β受体I（TBRI）激酶的负调节因子SMAD 7显著降低。当在骨髓组织微阵列中进行免疫化学检查时，还发现SMAD 7蛋白在MDS骨髓祖细胞中显著减少。SMAD 7在造血细胞中的表达减少导致TGF-β介导的基因转录增加，并且对TGF-β介导的抑制作用的敏感性增强。由于SMAD 7减少而增加的TGF-β信号传导可以被新型临床相关TBRI（ALK 5激酶）抑制剂LY-2157299有效抑制。LY-2157299可抑制TGF-β介导的SMAD 2活化和原代造血干细胞的造血抑制。此外，LY-2157299的体内施用改善了骨髓衰竭的TGF-β过表达转基因小鼠模型中的贫血。最重要的是，LY-2157199治疗刺激了原发性MDS骨髓标本的造血。这些研究表明，SMAD 7的减少是MDS中的一种新的分子改变，其通过激活造血细胞中的TGF-β信号传导而导致无效的造血。这些研究还说明了TBRI抑制剂在MDS中的治疗潜力。
Even though myelodysplastic syndromes are characterized by ineffective hematopoiesis, the molecular alterations that lead to marrow failure have not been well elucidated. We have previously shown that the myelosuppressive TGF-β pathway is constitutively activated in MDS progenitors. Since there is conflicting data about upregulation of extracellular TGF-b levels in MDS, we wanted to determine the molecular basis of TGF-β pathway overactivation and consequent hematopoietic suppression in this disease. We observed that SMAD7, a negative regulator of TGF-β receptor I (TBRI) kinase is markedly decreased in a large meta-analysis of gene expression studies from MDS marrow derived CD34+ cells. SMAD7 protein was also found to be significantly decreased in MDS marrow progenitors when examined immunohistochemically in a bone marrow tissue microarray. Reduced expression of SMAD7 in hematopoietic cells led to increased TGF-β mediated gene transcription and enhanced sensitivity to TGF-β mediated suppressive effects. The increased TGF-β signaling due to SMAD7 reduction could be effectively inhibited by a novel clinically relevant TBRI (ALK5 kinase) inhibitor, LY-2157299. LY-2157299 could inhibit TGF-β mediated SMAD2 activation and hematopoietic suppression in primary hematopoietic stem cells. Furthermore, in vivo administration of LY-2157299 ameliorated anemia in a TGF-β overexpressing transgenic mouse model of bone marrow failure. Most importantly, treatment with LY-2157199 stimulated hematopoiesis from primary MDS bone marrow specimens. These studies demonstrate that reduction in SMAD7 is a novel molecular alteration in MDS that leads to ineffective hematopoiesis by activating of TGF-β signaling in hematopoietic cells. These studies also illustrate the therapeutic potential of TBRI inhibitors in MDS.