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

A Kuhnl, Peter Valk, Mathijs Sanders, A Ivey, RK Hills, KI Mills, RE Gale, MF Kaiser, R Dillon, M Joannides, A Gilkes, T Haferlach, S Schnittger, E Duprez, DC Linch, Ruud Delwel, Bob Löwenberg, CD Baldus, E Solomon, AK BurnettD Grimwade

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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 relapserate (45% vs59%; P = .007) and a better over all survival (OS, 46% vs28%; 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 codownregulation 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 languageUndefined/Unknown
Pages (from-to)2985-2994
Number of pages10
JournalBlood
Volume125
Issue number19
DOIs
Publication statusPublished - 2015

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  • EMC MM-02-41-03

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