MALT‐1 as a novel therapeutic target for adult T‐cell leukemia.

Objectives: T‐cell receptor (TCR) signaling‐induced activation of NF‐κB requires assembly of the CARD11‐BCL10‐MALT‐1 complex and IκB kinase (IKK). Gain‐of‐function alterations in this component of the TCR/NF‐κB pathway are associated with the development of HTLV‐1‐driven adult T‐cell leukemia (ATL). We aimed to determine whether inhibition of MALT‐1‐mediated NF‐κB activation could have anti‐ATL activity. Methods: RT‐PCR, immunoblotting, and electrophoretic mobility shift assays were performed to assess expression levels of MALT‐1 and the intracellular signaling cascades. Cell proliferation, cell cycle progression, and apoptotic events were examined using WST‐8 assays, flow cytometry, and Hoechst 33342 staining. Results: MALT‐1 expression was upregulated in ATL‐derived T‐cell lines compared to that in normal PBMCs and uninfected or HTLV‐1‐transformed T‐cell lines. Targeting MALT‐1 with siRNA decreased cell proliferation. A MALT‐1 inhibitor (MI‐2) suppressed cleavage of the MALT‐1‐target protein, CYLD, and inhibited proliferation via G1 phase arrest. MI‐2 induced apoptosis through caspase‐3/8/9 activation and inhibited the phosphorylation of IKKα/β and IκBα, resulting in the accumulation of IκBα and suppression of NF‐κB‐DNA binding. Additionally, MI‐2 inhibited the expression of apoptosis‐ and cell cycle‐related proteins regulated by NF‐κB. Conclusions: MALT‐1 plays an important regulatory role in NF‐κB signaling during ATL‐genesis, and targeting MALT‐1 is a promising therapeutic strategy for this disease. [ABSTRACT FROM AUTHOR]