Tcl1 protein functions as an inhibitor of de novo DNA methylation in B-cell chronic lymphocytic leukemia (CLL)

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-02, Vol.109 (7), p.2555-2560
• Main Authors: Palamarchuk, Alexey, Yan, Pearlly S., Zanesi, Nicola, Wang, Linan, Rodrigues, Benjamin, Murphy, Mark, Balatti, Veronica, Bottoni, Arianna, Nazaryan, Natalya, Alder, Hansjuerg, Rassenti, Laura, Kipps, Thomas J., Freitas, Michael, Croce, Carlo M., Pekarsky, Yuri
• Format: Article
• Language: English
• Subjects: 3T3 cells; Acute myeloid leukemia; Antibodies; Biological Sciences; Cells; Chronic lymphatic leukemia; Chronic lymphocytic leukemia; Deoxyribonucleic acid; DNA; DNA Methylation; Enzymatic activity; Gene expression; Genetic mutation; Genetic vectors; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemogenesis; Lymphocytes B; Lymphocytes T; Lymphoma; Methylation; Mutation; Myelodysplastic syndrome; Myeloid leukemia; Oncogenes; Proteins; Proteomics; Proto-Oncogene Proteins - physiology; Transgenic animals; Transgenic mice
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1200003109

B-cell chronic lymphocytic leukemia (CLL) is the most common human leukemia. Deregulation of the T-cell leukemia/lymphoma 1 oncogene (TCL1) in mouse cells causes a CD5⁺ leukemia similar to aggressive human CLL To examine the mechanisms by which Tcl1 protein exerts its oncogenic activity in B cells, we performed proteomics experiments to identify its interacting partners. We found that Tcl1 physically interacts with de novo DNA methylthansferases Dnmt3A and Dnmt3B. We further investigated the effects of Tel1 up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3 A function. In addition, cells from TCL1 transgenic mice showed a significant decrease in DNA methylation compared with WT controls. Similarly, CLL samples with high Tcl1 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.