Abstract
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.
Highlights
T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease arising from early T-cell progenitors
To examine the effect of MI-2 on T-ALL cell growth, we evaluated the viability of CCRF and MOLT-4 cells treated with MI-2 using the Cell Counting Kit-8 (CCK-8) assay
E, the quantity and size of cell colonies were markedly decreased after a 12-day exposure to MI-2. These results demonstrate that MI-2 is preferentially cytotoxic for T-ALL cells
Summary
T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease arising from early T-cell progenitors. It accounts for approximately 15% of pediatric and 25% of adult ALL cases [1]. Current treatment is primarily based on high-intensity combination chemotherapy and comes with significant side effects [2]. The side effects on bone development and central nervous system in children should not be underestimated [3]. In addition to these side effects, the occurrence of relapse is another important challenge. Relapsed T-ALL patients are often associated with chemotherapy resistance and poor prognosis [4]. Developments of novel targeted therapeutics are urgently needed for treatment of T-ALL
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