Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition.

Autor:	Kong T; Division of Hematology, Department of Medicine., Laranjeira ABA; Division of Hematology, Department of Medicine., Collins TB; Division of Hematology, Department of Medicine., De Togni ES; Division of Hematology, Department of Medicine., Wong AJ; Division of Hematology, Department of Medicine., Fulbright MC; Division of Hematology, Department of Medicine., Ruzinova M; Department of Pathology and Immunology, and., Celik H; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO; and., Challen GA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO; and., Fisher DAC; Division of Hematology, Department of Medicine., Oh ST; Division of Hematology, Department of Medicine.; Department of Pathology and Immunology, and.; Immunomonitoring Laboratory, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2022 Jan 25; Vol. 6 (2), pp. 611-623.
DOI:	10.1182/bloodadvances.2020002804
Abstrakt:	Targeted inhibitors of JAK2 (eg ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone persists and remains susceptible to disease transformation. These observations suggest that targeting alternative dysregulated signaling pathways may provide therapeutic benefit. Previous studies identified NFκB pathway hyperactivation in myelofibrosis (MF) and secondary acute myeloid leukemia (sAML) that was insensitive to JAK2 inhibition. Here, we provide evidence that NFκB pathway inhibition via pevonedistat targets malignant cells in MPN patient samples as well as in MPN and patient-derived xenograft mouse models that are nonredundant with ruxolitinib. Colony forming assays revealed preferential inhibition of MF colony growth compared with normal colony formation. In mass cytometry studies, pevonedistat blunted canonical TNFα responses in MF and sAML patient CD34+ cells. Pevonedistat also inhibited hyperproduction of inflammatory cytokines more effectively than ruxolitinib. Upon pevonedistat treatment alone or in combination with ruxolitinib, MPN mouse models exhibited reduced disease burden and improved survival. These studies demonstrating efficacy of pevonedistat in MPN cells in vitro as well as in vivo provide a rationale for therapeutic inhibition of NFκB signaling for MF treatment. Based on these findings, a Phase 1 clinical trial combining pevonedistat with ruxolitinib has been initiated. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
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