Expression of p15ink4b gene during megakaryocytic differentiation of normal and myelodysplastic hematopoietic progenitors

被引:36
作者
Teofili, L
Martini, M
Di Mario, A
Rutella, S
Urbano, R
Luongo, M
Leone, G
Larocca, LM
机构
[1] Univ Cattolica Sacro Cuore, Inst Hematol, Rome, Italy
[2] Univ Cattolica Sacro Cuore, Inst Pathol, Rome, Italy
关键词
D O I
10.1182/blood.V98.2.495
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页码:495 / 497
页数:3
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