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 B 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 Tcl1 up-regulation on the enzymatic activity of Dnmt3A and found that Tcl1 overexpression drastically inhibits Dnmt3A 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 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.
Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University School of Medicine, Columbus, OH 43210, USA.
Alexey
A
Palamarchuk
Pearlly S
PS
Yan
Nicola
N
Zanesi
Linan
L
Wang
Benjamin
B
Rodrigues
Mark
M
Murphy
Veronica
V
Balatti
Arianna
A
Bottoni
Natalya
N
Nazaryan
Hansjuerg
H
Alder
Laura
L
Rassenti
Thomas J
TJ
Kipps
Michael
M
Freitas
Carlo M
CM
Croce
Yuri
Y
Pekarsky
D019175:DNA Methylation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000502:physiology*
D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human