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Blood. 2015 May 7;125(19):2985-94. doi: 10.1182/blood-2014-12-613703. Epub 2015 Mar 24.

Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia.

Author information

  • 1Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom; Department of Hematology and Oncology, Charité University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany;
  • 2Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
  • 3Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom;
  • 4Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom;
  • 5Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom;
  • 6Department of Haematology, University College London, London, United Kingdom;
  • 7Department of Hematology and Oncology, Charité University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany;
  • 8MLL Munich Leukemia Laboratory, Munich, Germany; and.
  • 9Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique UMR7258, Institut Paoli-Calmettes, Aix Marseille University, Marseille, France.

Abstract

The gene CXXC5 on 5q31 is frequently deleted in acute myeloid leukemia (AML) with del(5q), suggesting that inactivation of CXXC5 might play a role in leukemogenesis. Here, we investigated the functional and prognostic implications of CXXC5 expression in AML. CXXC5 mRNA was downregulated in AML with MLL rearrangements, t(8;21) and GATA2 mutations. As a mechanism of CXXC5 inactivation, we found evidence for epigenetic silencing by promoter methylation. Patients with CXXC5 expression below the median level had a lower relapse rate (45% vs 59%; P = .007) and a better overall survival (OS, 46% vs 28%; P < .001) and event-free survival (EFS, 36% vs 21%; P < .001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene-expression profiling, lower CXXC5 expression was associated with upregulation of cell-cycling genes and co-downregulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to affect the p53-dependent DNA damage response. In conclusion, our data suggest a tumor suppressor function of CXXC5 in AML. Inactivation of CXXC5 is associated with different leukemic pathways and defines an AML subgroup with better outcome.

© 2015 by The American Society of Hematology.

PMID:
25805812
[PubMed - indexed for MEDLINE]
PMCID:
PMC4463809
Free PMC Article
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