Zhou Li, Nguyen Aaron N, Sohal Davendra, Ying Ma Jing, Pahanish Perry, Gundabolu Krishna, Hayman Josh, Chubak Adam, Mo Yongkai, Bhagat Tushar D, Das Bhaskar, Kapoun Ann M, Navas Tony A, Parmar Simrit, Kambhampati Suman, Pellagatti Andrea, Braunchweig Ira, Zhang Ying, Wickrema Amittha, Medicherla Satyanarayana, Boultwood Jacqueline, Platanias Leonidas C, Higgins Linda S, List Alan F, Bitzer Markus, Verma Amit
Albert Einstein College of Medicine, Bronx, NY, USA.
Blood. 2008 Oct 15;112(8):3434-43. doi: 10.1182/blood-2008-02-139824. Epub 2008 May 12.
MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor-beta (TGF-beta) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34(+) cells, providing direct evidence of overactivation of TGF-beta pathway in this disease. Suppression of the TGF-beta signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-beta-mediated gene activation in BM stromal cells, and reverses TGF-beta-mediated cell-cycle arrest in BM CD34(+) cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-beta1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-beta signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.
骨髓增生异常综合征（MDS）的特征是造血功能无效，导致外周血细胞减少。由于对造血祖细胞发育异常生长的致病途径了解有限，有效治疗方法的开发受到阻碍。我们证明，smad2是转化生长因子-β（TGF-β）受体I激酶（TBRI）激活的下游介质，在MDS骨髓（BM）前体细胞中持续激活，并在MDS CD34(+)细胞的基因表达谱中过表达，为该疾病中TGF-β途径的过度激活提供了直接证据。通过慢病毒shRNA介导的TBRI下调抑制TGF-β信号传导，可导致MDS祖细胞体外造血增强。小分子抑制剂SD-208对TBRI（alk5）激酶的药理抑制作用，可抑制造血祖细胞中的smad2激活，抑制BM基质细胞中TGF-β介导的基因激活，并逆转BM CD34(+)细胞中TGF-β介导的细胞周期停滞。此外，在由TGF-β1的组成型肝脏表达产生的新型骨髓衰竭小鼠模型中，SD-208治疗可减轻贫血并刺激体内造血。此外，体外对TBRI激酶的药理抑制作用可导致不同形态学MDS亚型的造血增强。这些数据直接表明TGF-β信号传导参与无效造血的病理生物学过程，并确定TBRI为低危MDS的潜在治疗靶点。
