Expression of p15ink4b gene during megakaryocytic differentiation of normal and myelodysplastic hematopoietic progenitors
Expression of p15ink4b gene during megakaryocytic differentiation of normal and myelodysplastic hematopoietic progenitors
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DOI：
10.1182/blood.v98.2.495
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发表时间：
2001-07-15
期刊：
影响因子：
20.3
通讯作者：
Larocca, LM
中科院分区：
文献类型：
--
作者：
Teofili, L;Martini, M;Larocca, LM
在骨髓增生异常综合征(MDS)中，细胞周期蛋白依赖性激酶抑制因子p15(INK4B)(P15)的表达经常因为基因启动子的异常甲基化而降低；p15通常在巨核细胞分化过程中上调。推测在MDS患者中，p15甲基化和基因表达的失控导致有缺陷的巨核细胞生成。结果表明，在正常CD34(+)细胞中，自分泌增加的转化生长因子-β1刺激巨核细胞分化，而p15至少部分地介导了这一作用。这一依赖于转化生长因子-β1的途径在MDS CD34+祖细胞中由于p15甲基化而改变。脱甲基剂2-脱氧氮杂胞苷可以恢复p15基因的正常去甲基化状态，并增加其表达。然而，MDS CD34+细胞向巨核系分化较差。这些发现表明，p15甲基化发生在一个肿瘤克隆中，具有细胞增殖、存活和分化的严重缺陷，而使用去甲基化药物无法克服这一缺陷。(C)2001年，由美国血液病学会提供。
In myelodysplastic syndrome (MDS), the expression of the cyclin-dependent kinase inhibitor p15(INK4B) (p15) is frequently decreased because of the aberrant methylation of the gene promoter; p15 is normally up-regulated during megakaryocytic differentiation. It was hypothesized that p15 methylation and deregulation of gene expression contribute to defective megakaryocytopoiesis in patients with MDS. Here it is shown that the increasing autocrine production of TGF-beta1 stimulates megakaryocytic differentiation in normal CD34(+) cells and that p15 mediates, at least in part, this effect. This TGF-beta1-dependent pathway is altered in MDS CD34+ progenitors because of p15 methylation. The demethylating agent 2-deoxyAZAcytidin can restore the normal demethylated state of the p15 gene and increase its expression. Nevertheless, MDS CD34+ cells only poorly differentiate to the megakaryocytic lineage. These findings suggest that p15 methylation occurs in a neoplastic clone with a profound defect of cell proliferation, survival, and differentiation that cannot be overcome by using a demethylating drug. (C) 2001 by The American Society of Hematology.