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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.

Original publication

DOI

10.1182/blood-2014-12-613703

Type

Journal article

Journal

Blood

Publication Date

07/05/2015

Volume

125

Pages

2985 - 2994

Keywords

Adolescent, Adult, Aged, Biomarkers, Tumor, Carrier Proteins, Cell Cycle, Cohort Studies, DNA Methylation, Down-Regulation, Female, Follow-Up Studies, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Humans, Immunoenzyme Techniques, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Oligonucleotide Array Sequence Analysis, Prognosis, Promoter Regions, Genetic, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Survival Rate, Tumor Cells, Cultured, Wnt Proteins, Young Adult