GSE98206 MALT1 Inhibition Is Efficacious in Both Na ïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.

Contributors : Nakhle S Saba ; Deanna Wong ; Georges Tanios ; Jessica Iyer ; Patricia Lobelle-Rich ; Eman Dadashian ; Delong Liu ; Lorena Fontan ; Erik K Flemington ; Cydney Nichols ; Chingiz Underbayev ; Hana Safah ; Ari Melnick ; Adrian Wiestner ; Sarah E HermanSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensThe clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF- κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was eff ective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effe...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research