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CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin.

ABSTRACT: The discovery of JAK2 mutations in Philadelphia-negative myeloproliferative neoplasms has prompted investigators to evaluate mutation-targeted treatments to restore hematopoietic cell functions in these diseases. However, the results of the first clinical trials with JAK2 inhibitors are not as promising as expected, prompting a search for additional drugable targets to treat these disorders. In this paper, we used the hypomorphic Gata1(low) mouse model of primary myelofibrosis (PMF), the most severe of these neoplasms, to test the hypothesis that defective marrow hemopoiesis and development of extramedullary hematopoiesis in myelofibrosis is due to insufficient p27(Kip1) activity and is treatable by Aplidin, a cyclic depsipeptide that activates p27(Kip1) in several cancer cells. Aplidin restored expression of Gata1 and p27(Kip1) in Gata1(low) hematopoietic cells, proliferation of marrow progenitor cells in vitro and maturation of megakaryocytes in vivo (reducing TGF-beta/VEGF levels released in the microenvironment by immature Gata1(low) megakaryocytes). Microvessel density, fibrosis, bone growth, and marrow cellularity were normal in Aplidin-treated mice and extramedullary hematopoiesis did not develop in liver although CXCR4 expression in Gata1(low) progenitor cells remained low. These results indicate that Aplidin effectively alters the natural history of myelofibrosis in Gata1(low) mice and suggest this drug as candidate for clinical evaluation in PMF.

SUBMITTER: Verrucci M

PROVIDER: S-EPMC3780594 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin.

Verrucci Maria M Pancrazzi Alessandro A Aracil Miguel M Martelli Fabrizio F Guglielmelli Paola P Zingariello Maria M Ghinassi Barbara B D'Amore Emanuela E Jimeno José J Vannucchi Alessandro M AM Migliaccio Anna Rita AR

Journal of cellular physiology 20101101 2

The discovery of JAK2 mutations in Philadelphia-negative myeloproliferative neoplasms has prompted investigators to evaluate mutation-targeted treatments to restore hematopoietic cell functions in these diseases. However, the results of the first clinical trials with JAK2 inhibitors are not as promising as expected, prompting a search for additional drugable targets to treat these disorders. In this paper, we used the hypomorphic Gata1(low) mouse model of primary myelofibrosis (PMF), the most se ...[more]

PMID: 20458749

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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

CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin.

Publications

CXCR4-independent rescue of the myeloproliferative defect of the Gata1low myelofibrosis mouse model by Aplidin.

Similar Datasets

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