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

Objectives: T-cell receptor (TCR) signaling-induced activation of NF-kappa B requires assembly of the CARD11-BCL10-MALT-1 complex and I kappa B kinase (IKK). Gain-of-function alterations in this component of the TCR/NF-kappa B 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-kappa B 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 IKK alpha/beta and I kappa B alpha, resulting in the accumulation of I kappa B alpha and suppression of NF-kappa B-DNA binding. Additionally, MI-2 inhibited the expression of apoptosis- and cell cycle-related proteins regulated by NF-kappa B. Conclusions: MALT-1 plays an important regulatory role in NF-kappa B signaling during ATL-genesis, and targeting MALT-1 is a promising therapeutic strategy for this disease.