The requirement of MALT1 activity for the growth of adult T cell leukemia/lymphoma.

Adult T cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy with poor prognosis. Recurrent genetic alterations in T cell receptor (TCR) signaling components, including PLCG1, PRKCB, and CARD11, highlight the biological relevance of this pathway in ATL. We focused on mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), a key regulator of TCR signaling that functions through complex formation with CARD11 and BCL10, and developed a potent and selective MALT1 protease inhibitor, CRD-1441551. CRD-1441551 exhibited variable antitumor effects across ATL models both in vitro and in vivo. Among three ATL cell lines and five patient-derived xenograft models, two demonstrated marked sensitivity, three showed modest responses, and three were unresponsive. Notably, therapeutic responses were more frequently observed in models with constitutive MALT1 activation accompanied by enhanced MALT1-NF-κB signaling. These findings suggest that CRD-1441551 preferentially targets a subset of ATL, in which tumor growth is dependent on the MALT1-driven NF-κB pathway.