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Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model

Kubovcakova, Lucia and Lundberg, Pontus and Grisouard, Jean and Hao-Shen, Hui and Dirnhofer, Stephan and Wagner, Kay-Uwe and Skoda, Radek and Romanet, Vincent and Andraos-Rey, Rita and Murakami, Masato and Radimerski, Thomas (2012) Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. Blood. ISSN 0006-4971

Abstract

To establish a pre-clinical animal model for testing drugs with potential effects on MPN, we first performed a detailed phenotypic characterization of Cre-inducible transgenic JAK2-V617F mice. Deleting the conditional mouse Jak2 knockout alleles increased erythropoiesis and accentuated the polycythemia vera phenotype, but did not alter platelets and granulocyte levels. In a transplantation assay, JAK2-V617F positive bone marrow cells had an advantage over wild-type competitor cells. Using this competitive repopulation assay, we compared the effects of INC424 (ruxolitinib), a dual Jak1/Jak2 inhibitor, and hydroxyurea. Hydroxyurea led to weight loss, but did not reduce spleen weight. The hematologic parameters were lowered and a slight decrease of the mutant allele burden was noted. INC424 had little effect on body weight, but strongly decreased spleen size and rapidly normalized red cell and neutrophil parameters. No significant decrease in the mutant allele burden was observed. INC424 reduced phospho-Stat5 levels, whereas hydroxyurea strongly increased phospho-Stat5, most likely due to the elevated erythropoietin levels in response to the hydroxyurea induced anemia. This compensatory increase in JAK/STAT signaling may counteract the beneficial effects of cytoreduction at higher doses of hydroxyurea and represents an adverse effect that should be avoided

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6848

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