ASXL1 plays an important role in erythropoiesis.
ASXL1 plays an important role in erythropoiesis.
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ASXL1 在红细胞生成中发挥重要作用。
DOI：
10.1038/srep28789
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发表时间：
2016-06-29
影响因子：
4.6
通讯作者：
Yang FC
中科院分区：
文献类型：
--
作者：
Shi H;Yamamoto S;Sheng M;Bai J;Zhang P;Chen R;Chen S;Shi L;Abdel-Wahab O;Xu M;Zhou Y;Yang FC
ASXL 1突变存在于一系列预后不良的骨髓恶性肿瘤中。最近，我们报道了Asxl 1 +/−小鼠发生骨髓增生异常综合征（MDS）或MDS和骨髓增生性肿瘤（MPN）重叠疾病（MDS/MPN）。尽管红细胞成熟缺陷和贫血与MDS或MDS/MPN患者的预后相关，但ASXL 1在红细胞生成中的作用仍不清楚。在这里，我们发现，与WT ASXL 1的慢性粒单核细胞白血病（CMML）患者相比，ASXL 1突变的CMML患者表现出更严重的贫血，骨髓（BM）早期成红细胞比例显著增加，去核红细胞减少。在脐带血CD 34+细胞中ASXL 1的敲除减少了红细胞生成并损害了红细胞去核。一致地，VavCre+; Asxl 1f/f（Asxl 1f/f）小鼠的BM和脾脏具有比Asxl 1f/f对照少的红系祖细胞数量。与同窝对照组相比，Asxl 1 β/β小鼠BM中的成红细胞百分比也增加，红细胞去核减少。此外，Asxl 1 α/β成红细胞显示参与红细胞发育和稳态的基因表达改变，这与H3 K27 me 3和H3 K4 me 3水平降低有关。我们的研究揭示了ASXL 1在红细胞生成中的关键作用，并表明ASXL 1缺失阻碍了红细胞发育/成熟，这可能对MDS/MPN患者具有预后价值。
ASXL1 mutations are found in a spectrum of myeloid malignancies with poor prognosis. Recently, we reported that Asxl1+/− mice develop myelodysplastic syndrome (MDS) or MDS and myeloproliferative neoplasms (MPN) overlapping diseases (MDS/MPN). Although defective erythroid maturation and anemia are associated with the prognosis of patients with MDS or MDS/MPN, the role of ASXL1 in erythropoiesis remains unclear. Here, we showed that chronic myelomonocytic leukemia (CMML) patients with ASXL1 mutations exhibited more severe anemia with a significantly increased proportion of bone marrow (BM) early stage erythroblasts and reduced enucleated erythrocytes compared to CMML patients with WT ASXL1. Knockdown of ASXL1 in cord blood CD34+ cells reduced erythropoiesis and impaired erythrocyte enucleation. Consistently, the BM and spleens of VavCre+;Asxl1f/f (Asxl1∆/∆) mice had less numbers of erythroid progenitors than Asxl1f/f controls. Asxl1∆/∆ mice also had an increased percentage of erythroblasts and a reduced erythrocyte enucleation in their BM compared to littermate controls. Furthermore, Asxl1∆/∆ erythroblasts revealed altered expression of genes involved in erythroid development and homeostasis, which was associated with lower levels of H3K27me3 and H3K4me3. Our study unveils a key role for ASXL1 in erythropoiesis and indicates that ASXL1 loss hinders erythroid development/maturation, which could be of prognostic value for MDS/MPN patients.