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

In myelodysplastic syndrome (MDS), the expression of the cyclin-dependent kinase inhibitor p15ink4B (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-b1 stimulates megakaryocytic differentiation in normal CD341 cells and that p15 mediates, at least in part, this effect. This TGF-b1–dependent pathway is altered in MDS CD341 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 CD341 cells only poorly differentiate to the megakaryocytic lineage.Thesefindingssuggest that p15 methylation occurs in a neoplastic clone with a profound defect of cell proliferation,survival, anddifferentiation that cannot be overcome by using a demethylating drug. (Blood. 2001;98:495-497)