Tcl1 functions as a transcriptional regulator and is directly involved in the pathogenesis of CLL

被引:83
作者
Pekarsky, Yuri [1 ]
Palamarchuk, Alexey [1 ]
Maximov, Vadim [1 ]
Efanov, Alexey [1 ]
Nazaryan, Natalya [1 ]
Santanam, Urmila [1 ]
Rassenti, Laura [2 ]
Kipps, Thomas [2 ]
Croce, Carlo M. [1 ]
机构
[1] Ohio State Univ, Sch Med, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet,Human Canc Gen, Columbus, OH 43210 USA
[2] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1073/pnas.0810965105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-kappa B 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-kappa B 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-kappa B activity and inhibiting AP-1.
引用
收藏
页码:19643 / 19648
页数:6
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