Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis.

2.50
Hdl Handle:
http://hdl.handle.net/10541/72882
Title:
Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis.
Authors:
Strathdee, Gordon; Holyoake, Tessa L; Sim, Alyson; Parker, Anton; Oscier, David G; Melo, Junia V; Meyer, Stefan; Eden, Tim O B; Dickinson, Anne M; Mountford, Joanne C; Jorgensen, Heather G; Soutar, Richard; Brown, Robert
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. 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.
Affiliation:
Centre for Oncology and Applied Pharmacology, Cancer Research UK. G.R.Strathdee@newcastle.ac.uk
Citation:
Inactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis. 2007, 13 (17):5048-55 Clin. Cancer Res.
Journal:
Clinical Cancer Research
Issue Date:
1-Sep-2007
URI:
http://hdl.handle.net/10541/72882
DOI:
10.1158/1078-0432.CCR-07-0919
PubMed ID:
17785556
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorStrathdee, Gordon-
dc.contributor.authorHolyoake, Tessa L-
dc.contributor.authorSim, Alyson-
dc.contributor.authorParker, Anton-
dc.contributor.authorOscier, David G-
dc.contributor.authorMelo, Junia V-
dc.contributor.authorMeyer, Stefan-
dc.contributor.authorEden, Tim O B-
dc.contributor.authorDickinson, Anne M-
dc.contributor.authorMountford, Joanne C-
dc.contributor.authorJorgensen, Heather G-
dc.contributor.authorSoutar, Richard-
dc.contributor.authorBrown, Robert-
dc.date.accessioned2009-07-07T16:23:50Z-
dc.date.available2009-07-07T16:23:50Z-
dc.date.issued2007-09-01-
dc.identifier.citationInactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis. 2007, 13 (17):5048-55 Clin. Cancer Res.en
dc.identifier.issn1078-0432-
dc.identifier.pmid17785556-
dc.identifier.doi10.1158/1078-0432.CCR-07-0919-
dc.identifier.urihttp://hdl.handle.net/10541/72882-
dc.description.abstractPURPOSE: 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.en
dc.language.isoenen
dc.subjectLeukaemiaen
dc.subject.meshBlast Crisis-
dc.subject.meshCpG Islands-
dc.subject.meshDNA Methylation-
dc.subject.meshHomeodomain Proteins-
dc.subject.meshHumans-
dc.subject.meshLeukemia-
dc.subject.meshLeukemia, Lymphoid-
dc.subject.meshLeukemia, Myeloid-
dc.subject.meshPrognosis-
dc.titleInactivation of HOXA genes by hypermethylation in myeloid and lymphoid malignancy is frequent and associated with poor prognosis.en
dc.typeArticleen
dc.contributor.departmentCentre for Oncology and Applied Pharmacology, Cancer Research UK. G.R.Strathdee@newcastle.ac.uken
dc.identifier.journalClinical Cancer Researchen

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