Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis.
Clin Cancer Res
; 13(17): 5048-55, 2007 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-17785556
ABSTRACT
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. EXPERIMENTALDESIGN:
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.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Leucemia
/
Proteínas de Homeodominio
/
Metilación de ADN
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Clin Cancer Res
Asunto de la revista:
NEOPLASIAS
Año:
2007
Tipo del documento:
Article