Feb 11, 2021 · Simultaneous MALT1/MTORC1 inhibition abrogates survival feedback activation of MTORC1 and triggers synergistic killing of ABC-DLBCL. MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or …

We show that in CD79 mutant cells BTK is a crucial upstream regulator of MALT1, but dispensable in CARMA1 mutant ABC DLBCL. Combined inhibition of BTK by Ibrutinib and MALT1 by S-Mepazine additively impaired MALT1 cleavage activity and expression of …

MALT1 cleavage activity is linked to the pathogenesis of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL), a chemoresistant form of DLBCL. We developed a MALT1 activity assay and identified chemically diverse MALT1 inhibitors.

Nov 13, 2019 · MALT1 is aberrantly activated in ABC DLBCL by mutations in upstream genes in the BCR and TLR pathways (CD79A/B, CARD11, MYD88) and is critical for proliferation and survival. Recent studies by our lab, and others, identified inhibitors of MALT1 protease activity that revealed MALT1 is therapeutically targetable in ABC DLBCL.

Nov 15, 2022 · Genome sequence analysis data on these lymphomas suggest that the gene mutations of mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) -upstream molecules, such as CD79A/B and CARD11, eventually promotes the activation of MALT1's protease activity; this protease activity of MALT1 is known as a key growth or survival regulator ...

Here, we review recent advances in therapeutic targeting of MALT1 for ABC-DLBCL. Covalent and allosteric MALT1 protease inhibitors have been developed which inhibit growth of ABC-DLBCL in preclinical models, and two clinical MALT1 protease inhibitors are being developed in phase I clinical trials.

Jul 19, 2018 · Compound 3 revealed insights into the biology of MALT1 in ABC DLBCL, such as the role of MALT1 in driving JAK/STAT signaling and suppressing the type I IFN response and MHC class II expression, suggesting that MALT1 inhibition could prime lymphomas for immune recognition by cytotoxic immune cells.

Dec 23, 2012 · Chronic BCR signaling engages Syk, CD79A/B, Btk and PKCβ to induce the recruitment of the CARMA1-BCL10-MALT1 (CBM) complex that triggers IKK/NF-κB activation. Activation of the MALT1 protease promotes lymphoma survival by cleaving and inactivating negative regulators of NF-κB, e.g. A20 and RelB.

Simultaneous MALT1/MTORC1 inhibition abrogates survival feedback activation of MTORC1 and triggers synergistic killing of ABC-DLBCL. MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways.

Chronic BCR signaling engages the adaptors CD79A and CD79B in a Syk-dependent mechanism. Syk is constitutively active in many B-cell lymphomas and a clinical phase I/II trial using the Syk inhibitor fostamatinib disodium (FosD, AstraZeneca) shows some response also in DLBCL patients.