Loss of Forkhead box M1 promotes erythropoiesis through increased proliferation of erythroid progenitors.
Loss of Forkhead box M1 promotes erythropoiesis through increased proliferation of erythroid progenitors.
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DOI：
10.3324/haematol.2016.156257
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发表时间：
2017-05
期刊：
影响因子：
10.1
通讯作者：
Narla A
中科院分区：
文献类型：
--
作者：
Youn M;Wang N;LaVasseur C;Bibikova E;Kam S;Glader B;Sakamoto KM;Narla A
叉头盒M1（FOXM 1）属于叉头/翼状螺旋转录因子家族，调节增殖相关基因网络。它的异常上调已被证明是癌症进展的关键驱动因素和肿瘤发生的起始因子。FOXM 1也在干/祖细胞中高度表达并抑制其分化，表明FOXM 1在维持多能性中起作用。然而，FOXM 1调节人类干/祖细胞的确切分子机制仍然没有被表征。为了了解FOXM 1在正常造血中的作用，用FOXM 1短发夹核糖核酸（shRNA）慢病毒转导人脐带血CD 34+细胞。F0 XM 1的敲除导致红系细胞比髓系细胞增加2倍。此外，敲除FOXM 1增加了红系细胞中的溴脱氧尿苷（BrdU）掺入，表明红系祖细胞的增殖更大。我们还观察到，通过检查点激酶2（CHK 2）或细胞周期蛋白依赖性激酶1/2（CDK 1/2）的FOXM 1的缺陷性磷酸化以类似于FOXM 1敲低的方式增加红细胞群体。最后，我们发现FOXM 1的抑制剂，叉头结构域抑制剂-6（FDI-6），通过增加红细胞前体的增殖来增加红细胞数量。总的来说，我们的数据表明FOXM 1在正常人造血中的新功能。
Forkhead box M1 (FOXM1) belongs to the forkhead/winged-helix family of transcription factors and regulates a network of proliferation-associated genes. Its abnormal upregulation has been shown to be a key driver of cancer progression and an initiating factor in oncogenesis. FOXM1 is also highly expressed in stem/progenitor cells and inhibits their differentiation, suggesting that FOXM1 plays a role in the maintenance of multipotency. However, the exact molecular mechanisms by which FOXM1 regulates human stem/progenitor cells are still uncharacterized. To understand the role of FOXM1 in normal hematopoiesis, human cord blood CD34+ cells were transduced with FOXM1 short hairpin ribonucleic acid (shRNA) lentivirus. Knockdown of FOXM1 resulted in a 2-fold increase in erythroid cells compared to myeloid cells. Additionally, knockdown of FOXM1 increased bromodeoxyuridine (BrdU) incorporation in erythroid cells, suggesting greater proliferation of erythroid progenitors. We also observed that the defective phosphorylation of FOXM1 by checkpoint kinase 2 (CHK2) or cyclin-dependent kinases 1/2 (CDK1/2) increased the erythroid population in a manner similar to knockdown of FOXM1. Finally, we found that an inhibitor of FOXM1, forkhead domain inhibitor-6 (FDI-6), increased red blood cell numbers through increased proliferation of erythroid precursors. Overall, our data suggest a novel function of FOXM1 in normal human hematopoiesis.