RARβ2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia

Letetia C. Jones, Ayalew Tefferi, Gregory E. Idos, Takashi Kumagai, Wolf K. Hofmann, H. Phillip Koeffler

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Myelofibrosis with myeloid metaplasia (MMM) is a clonal stem-cell disorder that leads to ineffective hematopoiesis, bone marrow fibrosis, and extramedullary hematopoiesis. The molecular mechanisms underlying the development of this myeloproliferative syndrome are currently unknown. In order to identify tumor suppressor genes that may be involved in the disease process, we performed an analysis for loss of heterozygosity (LOH) in CD34+ cells from 29 patients with MMM. We observed a frequency of allelic loss on chromosomal arm 3p in 24% of cases. Detailed mapping of 3p revealed a distinct region of deletion at 3p24. Among the genes known to map within this region is the retinoic acid receptor-β (RARβ2) gene. To determine whether RARβ2 gene activity is diminished in this disease, we analysed its expression in CD34+ cells from 17 patients with MMM using quantitative PCR. Our results indicate that expression of RARβ2 is significantly decreased in 100% of patient samples compared to that in CD34+ cells from 10 normal individuals. Since allelic loss at 3p24 occurs in <25% of patients, we investigated the contribution of epigenetic modifications to RARβ2 inactivity. Using methylation-specific PCR, we found hypermethylation of RARβ2 in 16 of 18 patients (89%), while the methylated form of the gene was absent in CD34+ cells from nine normal individuals. Our results suggest that RARβ2 acts as a tumor suppressor gene in MMM and that epigenetic changes are the most significant determinants of RARβ2 gene activity in these patients.

Original languageEnglish (US)
Pages (from-to)7846-7853
Number of pages8
JournalOncogene
Volume23
Issue number47
DOIs
StatePublished - Oct 14 2004

Keywords

  • CD34+
  • Myelofibrosis
  • RARβ

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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