ArticleBlood advances2022
Pevonedistat targets malignant cells in myeloproliferative neoplasms in vitro and in vivo via NFκB pathway inhibition.
Article in Blood advances, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 16 citations in OpenAlex.
- Modulation of the sensitivity to ruxolitinib-mediated JAK2 inhibition by mutationally activated SHP2 exhibits cell context dependency in pre-clinical models of myeloproliferative neoplasms.bioRxiv : the preprint server for biology · 2026Article
- RSK1 is an exploitable dependency in myeloproliferative neoplasms and secondary acute myeloid leukemia.Nature communications · 2025Article
- In vivo ablation of NF-κB cascade effectors alleviates disease burden in myeloproliferative neoplasms.Blood · 2024Article
- Altered erythropoiesis via JAK2 and ASXL1 mutations in myeloproliferative neoplasms.Experimental hematology · 2024Article
- Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.The Journal of clinical investigation · 2024Article
- A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis.Therapeutic advances in hematology · 2024Article
- A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice.The Journal of clinical investigation · 2023Article
- Complementary and countervailing actions of Jak2 and Ikk2 in hematopoiesis in mice.Experimental hematology · 2023Article
- Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms.American journal of hematology · 2023Article
- Article
- DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.Nature cancer · 2023Article
- Proteomic identification of proliferation and progression markers in human polycythemia vera stem and progenitor cells.Blood advances · 2022Article
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
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.
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