This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Strathdee, G. Articles by Brown, R. Search for Related Content PubMed PubMed Citation Articles by Strathdee, G. Articles by Brown, R.

Inactivation of HOXA Genes by Hypermethylation in Myeloid and Lymphoid Malignancy is Frequent and Associated with Poor Prognosis

Authors' Affiliations: ¹ Centre for Oncology and Applied Pharmacology, Cancer Research U.K., Beatson Laboratories and ² Division of Cancer Sciences and Molecular Pathology, University of Glasgow, ³ Department of Haematology, Western Infirmary, Glasgow, United Kingdom; ⁴ Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom; ⁵ Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom; ⁶ Stem Cell and Leukaemia Proteomics Laboratory, Paterson Institute of Cancer Research and ⁷ Paediatric and Adolescent Oncology Unit, University of Manchester and Christie Hospital NHS Trust, Manchester, United Kingdom; and ⁸ Haematological Sciences, School of Clinical and Laboratory Sciences, The Medical School, Newcastle-upon-Tyne, United Kingdom

Requests for reprints: Gordon Strathdee, Life Knowledge Park, Institute of Human Genetics, Newcastle University, Central Parkway, Newcastle-upon-Tyne NE1 3BZ, United Kingdom. Phone: 44-191-241-8829; Fax: 44-191-241-8810; E-mail: G.R.Strathdee{at}newcastle.ac.uk.

Purpose: The HOX genes comprise a large family of homeodomain-containing transcription factors, present in four separate clusters, which are key regulators of embryonic development, hematopoietic differentiation, and leukemogenesis. We aimed to study the role of DNA methylation as an inducer of HOX gene silencing in leukemia.

Experimental Design: Three hundred and seventy-eight samples of myeloid and lymphoid leukemia were quantitatively analyzed (by COBRA analysis and pyrosequencing of bisulfite-modified DNA) for methylation of eight HOXA and HOXB cluster genes. The biological significance of the methylation identified was studied by expression analysis and through re-expression of HOXA5 in a chronic myeloid leukemia (CML) blast crisis cell line model.

Results: Here, we identify frequent hypermethylation and gene inactivation of HOXA and HOXB cluster genes in leukemia. In particular, hypermethylation of HOXA4 and HOXA5 was frequently observed (26-79%) in all types of leukemias studied. HOXA6 hypermethylation was predominantly restricted to lymphoid malignancies, whereas hypermethylation of other HOXA and HOXB genes was only observed in childhood leukemia. HOX gene methylation exhibited clear correlations with important clinical variables, most notably in CML, in which hypermethylation of both HOXA5 (P = 0.00002) and HOXA4 (P = 0.006) was strongly correlated with progression to blast crisis. Furthermore, re-expression of HOXA5 in CML blast crisis cells resulted in the induction of markers of granulocytic differentiation.

Conclusion: We propose that in addition to the oncogenic role of some HOX family members, other HOX genes are frequent targets for gene inactivation and normally play suppressor roles in leukemia development.

This article has been cited by other articles:

				P. Novak, T. J. Jensen, J. C. Garbe, M. R. Stampfer, and B. W. Futscher Stepwise DNA Methylation Changes Are Linked to Escape from Defined Proliferation Barriers and Mammary Epithelial Cell Immortalization Cancer Res., June 15, 2009; 69(12): 5251 - 5258. [Abstract] [Full Text] [PDF]

				S. Kamalakaran, J. Kendall, X. Zhao, C. Tang, S. Khan, K. Ravi, T. Auletta, M. Riggs, Y. Wang, A. Helland, et al. Methylation detection oligonucleotide microarray analysis: a high-resolution method for detection of CpG island methylation Nucleic Acids Res., May 27, 2009; (2009) gkp413v1. [Abstract] [Full Text] [PDF]

				X. Zhang, Z. Lian, C. Padden, M. B. Gerstein, J. Rozowsky, M. Snyder, T. R. Gingeras, P. Kapranov, S. M. Weissman, and P. E. Newburger A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster Blood, March 12, 2009; 113(11): 2526 - 2534. [Abstract] [Full Text] [PDF]

				C. Stresemann, I. Bokelmann, U. Mahlknecht, and F. Lyko Azacytidine causes complex DNA methylation responses in myeloid leukemia Mol. Cancer Ther., September 1, 2008; 7(9): 2998 - 3005. [Abstract] [Full Text] [PDF]

				E. Kavalerchik, D. Goff, and C. H.M. Jamieson Chronic Myeloid Leukemia Stem Cells J. Clin. Oncol., June 10, 2008; 26(17): 2911 - 2915. [Abstract] [Full Text] [PDF]

				S. P. Atkinson, C. M. Koch, G. K. Clelland, S. Willcox, J. C. Fowler, R. Stewart, M. Lako, I. Dunham, and L. Armstrong Epigenetic Marking Prepares the Human HOXA Cluster for Activation During Differentiation of Pluripotent Cells Stem Cells, May 1, 2008; 26(5): 1174 - 1185. [Abstract] [Full Text] [PDF]

				C. H. Jamieson Chronic Myeloid Leukemia Stem Cells Hematology, January 1, 2008; 2008(1): 436 - 442. [Abstract] [Full Text] [PDF]