Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition
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...
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Published in | Blood advances Vol. 6; no. 2; pp. 611 - 623 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
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United States
Elsevier Inc
25.01.2022
American Society of Hematology |
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Abstract | 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.
•Pevonedistat targets the NFκB pathway to inhibit growth of MPN and sAML cells.•Pevonedistat reduces disease burden in MPN mouse models.
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AbstractList | Pevonedistat targets the NFκB pathway to inhibit growth of MPN and sAML cells.
Pevonedistat reduces disease burden in MPN mouse models.
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. 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. 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.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. 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. •Pevonedistat targets the NFκB pathway to inhibit growth of MPN and sAML cells.•Pevonedistat reduces disease burden in MPN mouse models. [Display omitted] Abstract 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. |
Author | Fulbright, Mary C. Collins, Taylor B. Fisher, Daniel A.C. Oh, Stephen T. De Togni, Elisa S. Challen, Grant A. Wong, Abigail J. Ruzinova, Marianna Laranjeira, Angelo B.A. Kong, Tim Celik, Hamza |
AuthorAffiliation | 2 Department of Pathology and Immunology, and 3 Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO; and 4 Immunomonitoring Laboratory, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 1 Division of Hematology, Department of Medicine |
AuthorAffiliation_xml | – name: 2 Department of Pathology and Immunology, and – name: 4 Immunomonitoring Laboratory, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO – name: 3 Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO; and – name: 1 Division of Hematology, Department of Medicine |
Author_xml | – sequence: 1 givenname: Tim orcidid: 0000-0002-3240-8989 surname: Kong fullname: Kong, Tim organization: Division of Hematology, Department of Medicine – sequence: 2 givenname: Angelo B.A. surname: Laranjeira fullname: Laranjeira, Angelo B.A. organization: Division of Hematology, Department of Medicine – sequence: 3 givenname: Taylor B. surname: Collins fullname: Collins, Taylor B. organization: Division of Hematology, Department of Medicine – sequence: 4 givenname: Elisa S. surname: De Togni fullname: De Togni, Elisa S. organization: Division of Hematology, Department of Medicine – sequence: 5 givenname: Abigail J. surname: Wong fullname: Wong, Abigail J. organization: Division of Hematology, Department of Medicine – sequence: 6 givenname: Mary C. surname: Fulbright fullname: Fulbright, Mary C. organization: Division of Hematology, Department of Medicine – sequence: 7 givenname: Marianna orcidid: 0000-0002-0833-8335 surname: Ruzinova fullname: Ruzinova, Marianna organization: Department of Pathology and Immunology – sequence: 8 givenname: Hamza surname: Celik fullname: Celik, Hamza organization: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO – sequence: 9 givenname: Grant A. orcidid: 0000-0003-4669-8814 surname: Challen fullname: Challen, Grant A. organization: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO – sequence: 10 givenname: Daniel A.C. surname: Fisher fullname: Fisher, Daniel A.C. organization: Division of Hematology, Department of Medicine – sequence: 11 givenname: Stephen T. orcidid: 0000-0002-8564-5400 surname: Oh fullname: Oh, Stephen T. email: stoh@wustl.edu organization: Division of Hematology, Department of Medicine |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34644371$$D View this record in MEDLINE/PubMed |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Mass cytometry data will be made publicly available on Cytobank.org. RNA-sequencing data is deposited in NCBI GEO (accession number GSE184850). Data will be shared via e-mail to the corresponding author: stoh@wustl.edu. T.K., A.B.A.L., and T.B.C. contributed equally to this study. |
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Snippet | Targeted inhibitors of JAK2 (eg ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone persists... Abstract Targeted inhibitors of JAK2 (eg ruxolitinib) often provide symptomatic relief for myeloproliferative neoplasm (MPN) patients, but the malignant clone... Pevonedistat targets the NFκB pathway to inhibit growth of MPN and sAML cells. Pevonedistat reduces disease burden in MPN mouse models. Targeted inhibitors of... |
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SubjectTerms | Animals Cyclopentanes - therapeutic use Humans Leukemia, Myeloid, Acute - pathology Mice Myeloid Neoplasia Myeloproliferative Disorders - drug therapy Myeloproliferative Disorders - pathology Primary Myelofibrosis - pathology Pyrimidines |
Title | Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition |
URI | https://dx.doi.org/10.1182/bloodadvances.2020002804 https://www.ncbi.nlm.nih.gov/pubmed/34644371 https://www.proquest.com/docview/2582113623/abstract/ https://pubmed.ncbi.nlm.nih.gov/PMC8791597 |
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