title: Downregulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia.
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.
authors: Department 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;
authors: Andrea
authors: A
authors: Kühnl
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors: Peter J M
authors: PJ
authors: Valk
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors: Mathijs A
authors: MA
authors: Sanders
authors: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom;
authors: Adam
authors: A
authors: Ivey
authors: Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom;
authors: Robert K
authors: RK
authors: Hills
authors: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom;
authors: Ken I
authors: KI
authors: Mills
authors: Department of Haematology, University College London, London, United Kingdom;
authors: Rosemary E
authors: RE
authors: Gale
authors: Department of Hematology and Oncology, Charité University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany;
authors: Martin F
authors: MF
authors: Kaiser
authors: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom;
authors: Richard
authors: R
authors: Dillon
authors: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom;
authors: Melanie
authors: M
authors: Joannides
authors: Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom;
authors: Amanda
authors: A
authors: Gilkes
authors: MLL Munich Leukemia Laboratory, Munich, Germany; and.
authors: Torsten
authors: T
authors: Haferlach
authors: MLL Munich Leukemia Laboratory, Munich, Germany; and.
authors: Susanne
authors: S
authors: Schnittger
authors: Centre de Recherche en Cancérologie de Marseille, INSERM U1068, Centre National de la Recherche Scientifique UMR7258, Institut Paoli-Calmettes, Aix Marseille University, Marseille, France.
authors: Estelle
authors: E
authors: Duprez
authors: Department of Haematology, University College London, London, United Kingdom;
authors: David C
authors: DC
authors: Linch
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors: Ruud
authors: R
authors: Delwel
authors: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;
authors: Bob
authors: B
authors: Löwenberg
authors: Department of Hematology and Oncology, Charité University Hospital Berlin, Campus Benjamin Franklin, Berlin, Germany;
authors: Claudia D
authors: CD
authors: Baldus
authors: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom;
authors: Ellen
authors: E
authors: Solomon
authors: Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom;
authors: Alan K
authors: AK
authors: Burnett
authors: Department of Medical and Molecular Genetics, King's College London, Faculty of Life Sciences and Medicine, London, United Kingdom;
authors: David
authors: D
authors: Grimwade
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D015331:Cohort Studies; D019175:DNA Methylation; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007124:Immunoenzyme Techniques; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C540448:CXXC5 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051153:Wnt Proteins