Dataset Information

Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis.

ABSTRACT: Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of Abi1 in a novel mouse model leads to development of an MPN-like phenotype resembling human PMF. Abi1 loss resulted in a significant increase in the activity of the Src family kinases (SFKs), STAT3, and NF-?B signaling. We also observed impairment of hematopoietic stem cell self-renewal and fitness, as evidenced in noncompetitive and competitive bone marrow transplant experiments. CD34+ hematopoietic progenitors and granulocytes from patients with PMF showed decreased levels of ABI1 transcript as well as increased activity of SFKs, STAT3, and NF-?B. In aggregate, our data link the loss of Abi-1 function to hyperactive SFKs/STAT3/NF-?B signaling and suggest that this signaling axis may represent a regulatory module involved in the molecular pathophysiology of PMF.

SUBMITTER: Chorzalska A

PROVIDER: S-EPMC6236464 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bone marrow-specific loss of <i>ABI1</i> induces myeloproliferative neoplasm with features resembling human myelofibrosis.

Chorzalska Anna A Morgan John J Ahsan Nagib N Treaba Diana O DO Olszewski Adam J AJ Petersen Max M Kingston Nathan N Cheng Yan Y Lombardo Kara K Schorl Christoph C Yu Xiaoqing X Zini Roberta R Pacilli Annalisa A Tepper Alexander A Coburn Jillian J Hryniewicz-Jankowska Anita A Zhao Ting C TC Oancea Elena E Reagan John L JL Liang Olin O Kotula Leszek L Quesenberry Peter J PJ Gruppuso Philip A PA Manfredini Rossella R Vannucchi Alessandro Maria AM Dubielecka Patrycja M PM

Blood 20180913 19

Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showin ...[more]

PMID: 30213875

Similar Datasets

Project description:Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk MF. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT5, increased survival, and improved MF-associated disease features, including reduction of white blood cell counts, hematocrit, splenomegaly, and fibrosis. Fedratinib exerts off-target inhibitory activity against bromodomain-containing protein 4 (BRD4); combination JAK/STAT and BRD4 inhibition was shown to synergistically block NF-kB hyperactivation and inflammatory cytokine production, attenuating disease burden and reversing bone marrow fibrosis in animal models of MPNs. In patients, fedratinib is rapidly absorbed and dosed once daily (effective half-life 41 h). Fedratinib showed robust clinical activity in JAK-inhibitor-naïve patients and in patients with MF who were relapsed, refractory, or intolerant to prior ruxolitinib therapy. Fedratinib is effective regardless of JAK2 mutation status. Onset of spleen and symptom responses are typically seen within the first 1-2 months of treatment. The most common adverse events (AEs) with fedratinib are grades 1-2 gastrointestinal events, which are most frequent during early treatment and decrease over time. Treatment discontinuation due to hematologic AEs in clinical trials was uncommon (~3%). Suspected cases of Wernicke's encephalopathy were reported during fedratinib trials in ~1% of patients; thiamine levels should be monitored before and during fedratinib treatment as medically indicated. Phase III trials are ongoing to assess fedratinib effects on long-term safety, efficacy, and overall survival. The recent approval of fedratinib provides a much-needed addition to the limited therapeutic options available for patients with MF.

Dataset Information

Bone marrow-specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis.

Publications

Bone marrow-specific loss of <i>ABI1</i> induces myeloproliferative neoplasm with features resembling human myelofibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets