Down-regulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia
A partir de 529 échantillons prélevés dans la moelle osseuse de patients atteints d'une leucémie myéloïde aiguë, cette étude montre que la sous-expression du gène CXXC5 est associée à un pronostic favorable
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 down-regulated 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=0.007) and a better overall survival (OS: 46% vs 28%; P<0.001) and event-free survival (EFS: 36% vs 21%; P<0.001) at 5 years, independent of cytogenetic risk groups and known molecular risk factors. In gene expression profiling, lower CXXC5 expression was associated with up-regulation of cell cycling genes and co-down-regulation of genes implicated in leukemogenesis (WT1, GATA2, MLL, DNMT3B, RUNX1). Functional analyses demonstrated CXXC5 to inhibit leukemic cell proliferation and Wnt signaling and to impact 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.
Blood , résumé, 2014