1. CARMA1 is required for Notch1-induced NF-κB activation in SIL-TAL1-negative T cell acute lymphoblastic leukemia.
- Author
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Zhang, Ninghan, Xu, Jiawen, Wang, Rong, Pan, Ting, Zhang, Huanxin, Yin, Lingling, Yao, Yao, Xu, Linyan, Zhu, Shengyun, Wu, Qingyun, Li, Zhenyu, Liu, Xuejiao, Xu, Kailin, and Niu, Mingshan
- Subjects
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LYMPHOBLASTIC leukemia , *ACUTE leukemia , *INHIBITION of cellular proliferation , *CELLULAR signal transduction , *CELL survival - Abstract
The NF-κB signaling pathway is an important downstream pathway of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL) cells. However, the molecular mechanisms underlying the cascade activation of Notch1 in T-ALL cells are poorly understood. Here, we evaluated the role of CARMA1 in Notch1-induced NF-κB activation in T-ALL cells. CARMA1 was highly and specifically expressed in T-ALL cells and correlated with the prognosis of T-ALL patients. Interestingly, CARMA1 knockdown only inhibited the growth and proliferation of SIL-TAL1 fusion gene-negative T-ALL cells. In addition, CARMA1 knockdown arrested T-ALL cells at the G1 phase. Furthermore, CARMA1 knockdown significantly inhibited the proliferation of T-ALL cells in vivo and prolonged the survival of mice. Mechanistically, CARMA1 deficiency abolished Notch1-induced NF-κB transcriptional activation and significantly reduced expression levels of the NF-κB target genes c-Myc, Bcl-2, and CCR7. Taken together, these results of our study identify CARMA1 as one of the crucial mediators of Notch1-induced transformation of T-All cells, suggesting that CARMA1 is a promising therapeutic target for T-ALL due to its specific expression in lymphocytes. Key messages: CARMA1 contributes to cell survival only in SIL-TAL1 negative T-ALL cells. CARMA1 is a crucial mediator of Notch1-induced activation of NF-κB pathway. CARMA1 is a promising therapeutic target for T-ALL. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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