MALT1 Inhibition as a Therapeutic Strategy in T-Cell Acute Lymphoblastic Leukemia by Blocking Notch1-Induced NF-κB Activation

Frontiers in Oncology

Yao Yao¹  Rong Wang²  Ninghan Zhang²  Huihui Zhang²  Ting Pan²  Jiawen Xu²  Kailin Xu²  Huanxin Zhang²  Qingyun Wu²  Lingling Yin²  Mingshan Niu²  Zhenyu Li²  Xiaomin Zhong³  Xuejiao Liu⁴ 

[1] Blood Diseases Institute, Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China;Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China;Department of Medical Oncology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, China;Insititute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, China;

关键词: T-ALL;    MALT1;    MI-2;    Notch1;    NF-κB;   

DOI  :  10.3389/fonc.2020.558339

来源: DOAJ

【 摘 要 】

Current treatment of T-cell acute lymphoblastic leukemia (T-ALL) is primarily based on high-intensity combination chemotherapy, which has serious side effects. Therefore, developments of novel targeted therapeutics are urgently needed for treatment of T-ALL. In this study, we found that mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a novel promising therapeutic target for treatment of T-ALL. MALT1 inhibitor MI-2 significantly suppressed the cell growth, proliferation, and colony formation of T-ALL cells. Furthermore, MI-2 induced cell apoptosis of T-ALL via a mitochondrial-dependent pathway. In a T-ALL mouse model, MI-2 significantly reduced leukemic burden and prolonged the survival of leukemia-bearing mice. Mechanistically, MALT1 inhibition effectively blocked both baseline and Notch1-induced activation of nuclear factor κB pathway, which mediates T-ALL cell survival. In conclusion, our results highlight the potential role of MALT1 as an attractive target for treatment of T-ALL and support the potential of MI-2 or other MALT1 inhibitors to clinical trials in T-ALL.

【 授权许可】

Unknown