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Promoter hypermethylation silences expression of the HoxA4 gene and correlates with IgVh mutational status in CLL

Leukemia volume 20, pages 1326–1329 (2006)Cite this article

The human Hox genes are a large gene family, consisting of 39 members, which are all located in four gene clusters (HoxA–HoxD). They each encode homeodomain containing transcription factors, which are known to be key regulators of embryonic development.1 The Hox genes are also expressed in adult cells where they play important roles in the control of cellular differentiation, particularly during haematopoiesis.2 Several Hox gene family members (particularly those in the 5′ end of clusters, paralogs 9–13) are involved in leukaemia-associated translocations2 and aberrant expression of Hox genes is a common event in leukaemogenesis. Indeed overexpression of multiple Hox genes (particularly within the HoxA cluster) has been identified in both lymphoid and myeloid malignancies.2

Although the potential mechanisms leading to increased Hox gene expression have been widely studied, aberrant suppression of Hox genes (which are expressed in normal haematopoietic progenitors) has received little attention. Alterations in the patterns of DNA methylation are critical in the development of all types of cancer,3 and transcriptional repression owing to hypermethylation of promoter-associated CpG islands has been shown to inactivate many genes whose downregulation is known to be important in tumour development, both in haematological malignancies and in solid tumours.4, 5 All but one of the HoxA cluster genes (HoxA3) have CpG islands associated with their transcriptional start site (sequence derived from clones RP1-170O19 (AC004080), CTD-2536K9 (AC010990), RP1-167F23 (AC004079) in GenBank), suggesting that altered DNA methylation is a potential candidate mechanism for altered Hox gene expression in leukaemia.

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Acknowledgements

This work was supported by Cancer Research UK (GS, AS, RB) and by the Leukaemia Research Fund (AP, DO).

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  1. Cancer Research UK Beatson Laboratories, Centre for Oncology and Applied Pharmacology, Glasgow University, Glasgow, UK

    G Strathdee, A Sim & R Brown

  2. Department of Haematology, Royal Bournemouth, Hospital, Bournemouth, UK

    A Parker & D Oscier

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  1. G Strathdee
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Correspondence to G Strathdee.

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Strathdee, G., Sim, A., Parker, A. et al. Promoter hypermethylation silences expression of the HoxA4 gene and correlates with IgVh mutational status in CLL. Leukemia 20, 1326–1329 (2006). https://doi.org/10.1038/sj.leu.2404254

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