TET2 deficiency leads to stem cell factor-dependent clonal expansion of dysfunctional erythroid progenitors
TET2 deficiency leads to stem cell factor-dependent clonal expansion of dysfunctional erythroid progenitors
复制标题
TET2缺陷导致功能失调的红系祖细胞的干细胞因子依赖性克隆扩张
DOI：
10.1182/blood-2018-05-853291
复制
发表时间：
2018-11-29
期刊：
影响因子：
20.3
通讯作者：
An, Xiuli
中科院分区：
文献类型：
--
作者：
Qu, Xiaoli;Zhang, Shijie;An, Xiuli
骨髓增生异常综合征（MDS）是一类以无效造血为特征的克隆性造血干细胞疾病。贫血是MDS患者典型的血细胞减少表现，然而MDS中红细胞生成异常的分子机制仍未完全明确。近期研究表明，DNA双加氧酶TET2的杂合功能缺失突变是MDS中最常见的突变之一，且TET2缺乏会扰乱红细胞分化。然而，关于TET2在异常红细胞生成中作用的机制仍未完全阐明。在此，我们发现TET2缺乏最初会导致人红系集落形成单位（CFU - E）细胞依赖干细胞因子（SCF）的过度增殖以及分化受损，而c - Kit抑制剂可逆转这一现象。我们进一步表明，这是由于c - Kit磷酸化增加，同时伴有c - Kit负调节因子磷酸酶SHP - 1表达降低所致。在后期，TET2缺乏导致一类祖细胞群体积累，这类细胞表达正常CFU - E细胞的特征性表面标志物，但功能却有所不同。与仅需促红细胞生成素（EPO）即可增殖的正常CFU - E细胞不同，这些异常祖细胞需要SCF和EPO，且分化受损。我们将这类祖细胞群体称为“标记CFU - E”细胞。我们进一步发现，“标记CFU - E”细胞中AXL表达增加，且AXL表达增加导致AKT和ERK的激活增强。此外，AXL抑制剂可部分挽救“标记CFU - E”细胞异常的增殖和分化。我们的研究结果证明了TET2在红细胞生成中的重要作用，并揭示了TET2缺乏导致无效红细胞生成的此前未知的机制。
Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis. Anemia is the defining cytopenia of MDS patients, yet the molecular mechanisms for dyserythropoiesis in MDSs remain to be fully defined. Recent studies have revealed that heterozygous loss-of-function mutation of DNA dioxygenase TET2 is 1 of the most common mutations in MDSs and that TET2 deficiency disturbs erythroid differentiation. However, mechanistic insights into the role of TET2 on disordered erythropoiesis are not fully defined. Here, we show that TET2 deficiency leads initially to stem cell factor (SCF)-dependent hyperproliferation and impaired differentiation of human colony-forming unit-erythroid (CFU-E) cells, which were reversed by a c-Kit inhibitor. We further show that this was due to increased phosphorylation of c-Kit accompanied by decreased expression of phosphatase SHP-1, a negative regulator of c-Kit. At later stages, TET2 deficiency led to an accumulation of a progenitor population, which expressed surface markers characteristic of normal CFU-E cells but were functionally different. In contrast to normal CFU-E cells that require only erythropoietin (EPO) for proliferation, these abnormal progenitors required SCF and EPO and exhibited impaired differentiation. We termed this population of progenitors "marker CFU-E" cells. We further show that AXL expression was increased in marker CFU-E cells and that the increased AXL expression led to increased activation of AKT and ERK. Moreover, the altered proliferation and differentiation of marker CFU-E cells were partially rescued by an AXL inhibitor. Our findings document an important role for TET2 in erythropoiesis and have uncovered previously unknown mechanisms by which deficiency of TET2 contributes to ineffective erythropoiesis.