RÉSUMÉ
BACKGROUND: More than 80% of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) patients harbor the (nucleophosmin) NPM1-ALK fusion gene t(2;5) chromosomal translocation. We evaluated the preclinical and clinical efficacy of ceritinib treatment of this aggressive lymphoma. MATERIALS AND METHODS: We studied the effects of ceritinib treatment in NPM1-ALK+ T-cell lymphoma cell lines in vitro and on tumor size and survival advantage in vivo utilizing tumor xenografts. We treated an NPM1-ALK+ ALCL patient with ceritinib. We reviewed all hematologic malignancies profiled by a large hybrid-capture next-generation sequencing (NGS)-based comprehensive genomic profiling assay for ALK alterations. RESULTS: In our in vitro experiments, ceritinib inhibited constitutive activation of the fusion kinase NPM1-ALK and downstream effector molecules STAT3, AKT, and ERK1/2, and induced apoptosis of these lymphoma cell lines. Cell cycle analysis following ceritinib treatment showed G0/G1 arrest with a concomitant decrease in the percentage of cells in S and G2/M phases. Further, treatment with ceritinib in the NPM1-ALK+ ALCL xenograft model resulted in tumor regression and improved survival. Of 19 272 patients with hematopoietic diseases sequenced, 58 patients (0.30%) harbored ALK fusions that include histiocytic disorders, multiple myeloma, B-cell neoplasms, Castleman's disease, and juvenile xanthogranuloma. A multiple relapsed NPM1-ALK+ ALCL patient treated with ceritinib achieved complete remission with ongoing clinical benefit to date, 5 years after initiation of therapy. CONCLUSIONS: This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies.
Sujet(s)
Lymphome à grandes cellules anaplasiques , Kinase du lymphome anaplasique/génétique , Humains , Lymphome à grandes cellules anaplasiques/traitement médicamenteux , Lymphome à grandes cellules anaplasiques/génétique , Nucléophosmine , Études prospectives , Pyrimidines , Récepteurs à activité tyrosine kinase/génétique , SulfonesRÉSUMÉ
The nuclear genome drives differences in immune cell populations and differentiation potentials, in part regulated by changes in metabolism. Despite this connection, the role of mitochondrial DNA (mtDNA) polymorphisms (SNP) in this process has not been examined. Using mitochondrial nuclear exchange (MNX) mice, we and others have shown that mtDNA strongly influences varying aspects of cell biology and disease. Based upon an established connection between mitochondria and immune cell polarization, we hypothesized that mtDNA SNP alter immune cell development, trafficking, and/or differentiation. Innate and adaptive immune cell populations were isolated and characterizated from the peritoneum and spleen. While most differences between mouse strains are regulated by nuclear DNA (nDNA), there are selective changes that are mediated by mtDNA differences (e.g., macrophage (CD11c) differentiation), These findings highlight how nuclear-mitochondrial crosstalk may alter pathology and physiology via regulation of specific components of the immune system.