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

Oncogene volume 23, pages 7846–7853 (2004)Cite this article

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.

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Acknowledgements

This study was supported by the generous gift from the Phylis and Brain Harvey Fund as well as an NIH grant. This work was supported by grants from the National Institutes of Health to HPK and LCJ (T32 CA-75956) and the Brian and Phylis Harvey Fund. HPK is a member of the Jonsson Comprehensive Cancer Center and the Molecular Biology Institute of UCLA and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, 90048, CA, USA

    Letetia C Jones, Gregory E Idos, Takashi Kumagai & H Phillip Koeffler

  2. Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, 55905, MN, USA

    Ayalew Tefferi

  3. Department of Hematology, University Hospital, Frankfurt/Main, 60596, Germany

    Wolf-K Hofmann

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  1. Letetia C Jones
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Correspondence to Letetia C Jones.

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Jones, L., Tefferi, A., Idos, G. et al. RARβ2 is a candidate tumor suppressor gene in myelofibrosis with myeloid metaplasia. Oncogene 23, 7846–7853 (2004). https://doi.org/10.1038/sj.onc.1207510

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