TcM protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

摘要

B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. Deregulation of the T-cell teukemia/lymphoma 1 oncogene (TCL1) in mouse B cells causes a CD5~+ leukemia similar to aggressive human CLL. To examine the mechanisms by which TcM protein exerts its oncogenic activity in B cells, we performed proteomics experiments to identify its interacting partners. We found that Tel1 physically interacts with de novo DNA methylthansferases Dnmt3A and Dnmt3B. We further investigated the effects of TcM up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3 A function. In addition, B cells from TCL1 transgenic mice showed a significant decrease in DNA methylation compared with WT controls. Similarly, CLL samples with high Tell expression showed a decrease in DNA methylation compared with CLL samples with low Tcl1 expression. Given the previous reports of inactivating mutations of DNMT3A in acute myelogenous leukemia and myelodysplastic syndrome, our results suggest that inhibition of de novo DNA methylation may be a common oncogenic mechanism in leukemogenesis.