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

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

Blood (2015-03-26)
Andrea Kühnl, Peter J M Valk, Mathijs A Sanders, Adam Ivey, Robert K Hills, Ken I Mills, Rosemary E Gale, Martin F Kaiser, Richard Dillon, Melanie Joannides, Amanda Gilkes, Torsten Haferlach, Susanne Schnittger, Estelle Duprez, David C Linch, Ruud Delwel, Bob Löwenberg, Claudia D Baldus, Ellen Solomon, Alan K Burnett, David Grimwade
要旨

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.

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α,α-Dicyanoethyl acetate, 98%