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

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

PROVIDER: PRJNA766651 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16089226_1.fastq.gz	Fastqsanger.gz
	SRR16089226_2.fastq.gz	Fastqsanger.gz
	SRR16089227_1.fastq.gz	Fastqsanger.gz
	SRR16089227_2.fastq.gz	Fastqsanger.gz
	SRR16089228_1.fastq.gz	Fastqsanger.gz

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

Project description:Targeted inhibitors of JAK2 (e.g. 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 syngeneic MPN and patient-derived xenograft mouse models that is non-redundant with ruxolitinib. Colony forming assays revealed preferential inhibition of MF colony growth compared to normal colony formation. In mass cytometry studies, pevonedistat blunted canonical TNF⍺ 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 I clinical trial combining pevonedistat with ruxolitinib has been initiated.

2021-12-01 | GSE184850 | GEO

Myelodysplastic/myeloproliferative neoplasms

Project description:This SuperSeries is composed of the following subset Series: GSE21948: High Density custom Agilent 44K CGH array analysis of 7q and TET2 region in myelodysplastic/myeloproliferative neoplasms GSE21990: Affymetrix SNP 6.0 array data for myelodysplastic/myeloproliferative neoplasms Refer to individual Series

2010-06-30 | E-GEOD-21991 | biostudies-arrayexpress

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

Project description: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.

| S-EPMC8791597 | biostudies-literature

Pathophysiology of arterial cardiovascular events in patients with JAK2V617F myeloproliferative neoplasms

Project description:Cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms. Their mechanisms are poorly understood. To investigate the role of microvesicles in these events, we performed a proteomic analysis of microvesicles derived from red blood cells from mice with a myeloproliferative neoplasms (Jak2V617F Flex/WT ;VE-cadherin-Cre) vs. littermate controls.

2020-02-17 | PXD014451 | Pride

Comprehensive profiing of clinical JAK inhibitors in myeloproliferative neoplasms

Project description:Comprehensive profiing of clinical JAK inhibitors in myeloproliferative neoplasms

2023-05-24 | GSE229712 | GEO

Targeting the CALR Interactome in Myeloproliferative Neoplasms

Project description:Targeting the CALR Interactome in Myeloproliferative Neoplasms

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Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predispose to myeloproliferative neoplasms

Project description:Genome-wide association study of JAK2 V617F negative myeloproliferative neoplasms consisting of 524 cases at stage 1

2015-02-20 | E-MTAB-3340 | biostudies-arrayexpress

Targeting CHAF1B enhances interferon activity in myeloproliferative neoplasms

Project description:Interferons (IFNs) are cytokines with potent anti-neoplastic properties and significant clinical activity in the treatment of myeloproliferative neoplasms (MPNs). The use of pegylated IFN for the treatment of MPNs has been of particular interest, with several clinical trials establishing clinical responses. Here we demonstrate that chromatin assembly factor 1 subunit B (CHAF1B) is overexpressed in MPN patients. Targeted silencing of CHAF1B enhances transcription of IFN-stimulated genes and promotes IFN-dependent anti-neoplastic effects against MPN patient-derived cells. Our findings suggest that targeting CHAF1B in combination with IFN therapy may offer an avenue for the development of effective combination therapies for the treatment of MPNs.

2023-05-15 | PXD037376 | Pride

Talarmain2022- Model of JAK2/TET2/HOXA9 in myeloproliferative neoplasms

Project description:Model describing how HOXA9 may control the evolution of myeloproliferative neoplasms by integrating the orders of JAK2 and TET2 mutation

2023-03-17 | MODEL2212110001 | BioModels

A Unique Signaling Feedback Circuit Defines Interferon Responses in Myeloproliferative Neoplasms

Project description:Type I interferons (IFNs) are key initiators and effectors of the immune response against malignant cells and can also directly inhibit tumor growth. IFN is highly effective in the treatment of myeloproliferative neoplasms (MPNs), but the mechanisms of action are unclear and it remains unknown why some patients respond to IFN therapy and others do not. We have identified and characterized a novel pathway involving PKC upstream of the kinase ULK1. Engagement of the Type I IFN receptor triggers PKC-dependent phosphorylation of ULK1 on serines 341 and 495, required for subsequent engagement of p38 MAPK that regulates transcription of IFN-stimulated genes and subsequent growth inhibitory responses. We show that this pathway is essential for IFN-suppressive effects on primary malignant erythroid precursors from patients with MPNs in vitro, while increased levels of ULK1 and p38 MAPK correlate with clinical response to IFN therapy in MPN patients. IFN treatment also induces cleavage/activation of the ULK1-interacting ROCK1/2 proteins in vivo, triggering a negative feedback loop that suppresses IFN responses. Both ROCK homologs are overexpressed in MPN patients and their genetic or pharmacological inhibition enhances IFN-anti-neoplastic responses in malignant erythroid progenitors from MPN patients. Together, our results identify activation of the PKC-ULK1-p38 MAPK cascade as a key and essential component for the IFN-response, regulated by a feedback loop involving ROCK1/2. These findings suggest the clinical potential of pharmacological inhibition of ROCK1/2 in combination with IFN-therapy for the treatment of MPN patients.

2022-01-10 | PXD021748 | Pride

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