Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes.
Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes.
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病理生物学假性缺氧是骨髓增生异常综合征的潜在机制
DOI：
10.1158/2159-8290.cd-17-1203
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发表时间：
2018-11
期刊：
影响因子：
28.2
通讯作者：
Huang G
中科院分区：
文献类型：
--
作者：
Hayashi Y;Zhang Y;Yokota A;Yan X;Liu J;Choi K;Li B;Sashida G;Peng Y;Xu Z;Huang R;Zhang L;Freudiger GM;Wang J;Dong Y;Zhou Y;Wang J;Wu L;Bu J;Chen A;Zhao X;Sun X;Chetal K;Olsson A;Watanabe M;Romick-Rosendale LE;Harada H;Shih LY;Tse W;Bridges JP;Caligiuri MA;Huang T;Zheng Y;Witte DP;Wang QF;Qu CK;Salomonis N;Grimes HL;Nimer SD;Xiao Z;Huang G
骨髓增生异常综合征(MDS)是一种用传统疗法无法治愈的异质性造血疾病。随着全球人口老龄化，这一发病率正在上升。虽然在MDS患者中发现了许多遗传、表观遗传、剪接和代谢异常，但它们的临床特征非常相似。在这里，我们证明了低氧诱导因子1α(HIF1a)信号的非低氧激活是诱导发育异常和细胞减少的MDS表型的必要条件和充分条件。HIF1a转录信号通常在MDS患者的骨髓干/祖细胞中激活。与MDS相关的主要突变(DNMT3A、TET2、ASXL1、RUNX1和MLL1)激活HIF1a签名。虽然在造血细胞中诱导激活HIF1a信号足以诱导MDS表型，但遗传和化学抑制HIF1a信号都可以挽救MDS小鼠模型中的MDS表型。这些发现表明，HIF1a是MDS的中心病理生物学介质，并且是广泛MDS患者的有效治疗靶点。我们表明，HIF1a信号的失调可以通过作为MDS驱动突变的信号漏斗来产生与临床相关的MDS表型多样性。这可能解决基因类型和表型之间的脱节，并为各种驱动突变如何导致常见的MDS表型提供新的线索。
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic disorders that are incurable with conventional therapy. The incidence is increasing with global population ageing. Although many genetic, epigenetic, splicing, and metabolic aberrations have been identified in MDS patients, their clinical features are quite similar. Here we show that hypoxia-independent activation of hypoxia-inducible factor 1α (HIF1A) signaling is both necessary and sufficient to induce dysplastic and cytopenic MDS phenotypes. The HIF1A transcriptional signature is generally activated in MDS-patient bone-marrow stem/progenitors. Major MDS-associated mutations (Dnmt3a, Tet2, Asxl1, Runx1, and Mll1) activate the HIF1A signature. While inducible activation of HIF1A signaling in hematopoietic cells is sufficient to induce MDS phenotypes, both genetic and chemical inhibition of HIF1A signaling rescues MDS phenotypes in a mouse model of MDS. These findings reveal HIF1A as a central pathobiologic mediator of MDS, and as an effective therapeutic target for a broad spectrum of MDS patients. We showed that dysregulation of HIF1A signaling could generate the clinically-relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS driver-mutations. This could resolve the disconnection between genotypes and phenotypes, and provide a new clue as to how a variety of driver-mutations cause common MDS phenotypes.