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

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,...

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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
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Summary: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.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1200003109