Effects of chromatin-modifying agents on CD34+ cells from patients with idiopathic myelofibrosis

Jun Shi, Yan Zhao, Takefumi Ishii, Wenyang Hu, Selcuk Sozer, Wei Zhang, Edward Bruno, Valerie Lindgren, Mingjiang Xu, Ronald Hoffman

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Idiopathic myelofibrosis (IM) is likely the consequence of both the acquisition of genetic mutations and epigenetic changes that silence critical genes that control cell proliferation, differentiation, and apoptosis. We have explored the effects of the sequential treatment with the DNA methyltransferase inhibitor, decitabine [5-aza-2′-deoxycytidine (5azaD)], followed by the histone deacetylase inhibitor, trichostatin A (TSA), on the behavior of IM CD34+ cells. Unlike normal CD34+ cells where 5azaD/TSA treatment leads to the expansion of CD34+ cells and marrow-repopulating cells, treatment of IM CD34+ cells results in a reduction of the number of total cells, CD34+ cells, and assayable hematopoietic progenitor cells (HPC). In IM, HPCs are either heterozygous or homozygous for the JAK2V617F mutation or possess wild-type JAK2 in varying proportions. Exposure of IM CD34+ cells to 5azaD/TSA resulted in a reduction of the proportion of JAK2V617Fpositive HPCs in 83% of the patients studied and the reduction in the proportion of homozygous HPCs in 50% of the patients. 5azaD/TSA treatment led to a dramatic reduction in the number of HPCs that contained chromosomal abnormalities in two JAK2V617F-negative IM patients. IM is characterized by constitutive mobilization of HPCs, which has been partly attributed to decreased expression of the chemokine receptor CXCR4. Treatment of IM CD34+ cells with 5azaD/TSA resulted in the up-regulation of CXCR4 expression by CD34+ cells and restoration of their migration in response to SDF-1. These data provide a rationale for sequential therapy with chromatin-modifying agents for patients with IM.

Original languageEnglish (US)
Pages (from-to)6417-6424
Number of pages8
JournalCancer Research
Volume67
Issue number13
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Shi, J., Zhao, Y., Ishii, T., Hu, W., Sozer, S., Zhang, W., Bruno, E., Lindgren, V., Xu, M., & Hoffman, R. (2007). Effects of chromatin-modifying agents on CD34+ cells from patients with idiopathic myelofibrosis. Cancer Research, 67(13), 6417-6424. https://doi.org/10.1158/0008-5472.CAN-07-0572