Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL.
B cell chronic lymphocytic leukemia (B-CLL) is the most common human leukemia. Deregulation of the T cell leukemia/lymphoma 1 (TCL1) oncogene in mouse B cells causes a CD5-positive leukemia similar to aggressive human B-CLLs. To examine the mechanisms by which Tcl1 protein exerts oncogenic activity in B cells, we investigated the effect of Tcl1 expression on NF-kappaB and activator protein 1 (AP-1) activity. We found that Tcl1 physically interacts with c-Jun, JunB, and c-Fos and inhibits AP-1 transcriptional activity. Additionally, Tcl1 activates NF-kappaB by physically interacting with p300/CREB binding protein. We then sequenced the TCL1 gene in 600 B-CLL samples and found 2 heterozygous mutations: T38I and R52H. Importantly, both mutants showed gain of function as AP-1 inhibitors. The results indicate that Tcl1 overexpression causes B-CLL by directly enhancing NF-kappaB activity and inhibiting AP-1.
Pekarsky
Yuri
Y
Human Cancer Genetics Program, Comprehensive Cancer Center, Department of Molecular Virology, Immunology, and Medical Genetics, School of Medicine, Ohio State University, Columbus, OH 43210, USA. pekarsky.yuri@osumc.edu
Palamarchuk
Alexey
A
Maximov
Vadim
V
Efanov
Alexey
A
Nazaryan
Natalya
N
Santanam
Urmila
U
Rassenti
Laura
L
Kipps
Thomas
T
Croce
Carlo M
CM
D000818:Animals; D017209:Apoptosis; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D041681:NIH 3T3 Cells; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; C090851:TCL1A protein, human; D018808:Transcription Factor AP-1; D050880:p300-CBP Transcription Factors