Giridhar Mudduluru's research while affiliated with University of Kansas Medical Center and other places

Anaplastic large cell lymphoma (ALCL) represents a rare and aggressive subtype of CD30-positive peripheral T-Cell lymphoma which accounts for 5-10% of non-Hodgkin lymphomas in adults and 10-30% in children. More than 80% of ALK-positive ALCLs hallmarked by fusion gene NPM1-ALK generated by t(2;5) chromosomal translocation. The fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for oncogenicity. The current therapeutic approaches used for the treatment of ALK-positive ALCLs has limited effectiveness with poor outcomes. Celastrol, a triterpene molecule extracted from the Chinese herbal plant Tripterygium wilfordii Hook F, blocks the interaction between HSP90 and CDC37 and triggers the degradation of its dependent client protein kinases. In this study, we tested the fusion oncogene NPM1-ALK dependency on co-chaperone CDC37 using celastrol in ALCL cells. Celastrol treatment resulted in degradation of NPM1-ALK fusion kinase which inhibited downstream survival signaling pathways including AKT, ERK1/2, STAT3, and induced apoptosis. Celastrol also decreased ALCL cell proliferation and downregulated CD30 expression. In summary, our results demonstrate targeting CDC37 using celastrol is a novel therapeutic approach to induce apoptosis in ALCL cells expressing NPM1-ALK and warrants developing future therapeutic intervention strategies.

Epstein–Barr virus (EBV) is directly implicated in several B-cell lymphoid malignancies. EBV-associated lymphomas are characterized by prominent activation of the NF-κB pathway and targeting this pathway establishes a rationale for a therapeutic approach. The ubiquitin/proteasome signaling plays an essential role in the regulation of the NF-κB pathway. Ixazomib is an FDA-approved, orally bioavailable proteasome inhibitor. Here we report the first preclinical evaluation of ixazomib-mediated growth-inhibitory effects on EBV-infected B-lymphoblastoid cell lines Raji and Daudi. Ixazomib induced apoptosis in these cell lines in a dose-dependent manner. Cell-cycle analysis demonstrated ixazomib treatment induced cell-cycle arrest at the G2–M phase with a concomitant decrease in G0–G1 and S phases. The results further revealed an increase in p53, p21, and p27 levels and a decrease in survivin and c-Myc protein levels. Mechanistically, ixazomib treatment resulted in the accumulation of polyubiquitinated proteins, including phosphorylated IκBα with a significant reduction of p65 subunit nuclear translocation. Altogether, our preclinical data support the rationale for in vivo testing of ixazomib in EBV-associated B-cell neoplasms. Implications This preclinical study supports the use of oral proteasome inhibitor ixazomib for targeting NF-κB signaling in the treatment of EBV-associated B-cell neoplasms. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/4/839/F1.large.jpg.