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

Lucia Kubovcakova, Pontus Lundberg, Jean Grisouard, Hui Hao-Shen, Vincent Romanet, Rita Andraos, Masato Murakami, Stephan Dirnhofer, Kay Uwe Wagner, Thomas Radimerski, Radek C. Skoda

Research output: Contribution to journalArticle

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Abstract

To establish a preclinical animal model for testing drugs with potential effects on myeloproliferative neoplasms (MPNs), 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 platelet or granulocyte levels. In a transplantation assay, JAK2-V617F BM 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 (HU). HU 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 RBC and neutrophil parameters. No significant decrease in the mutant allele burden was observed. INC424 reduced the phospho-Stat5 levels, whereas HU strongly increased phospho-Stat5, most likely because of the elevated erythropoietin levels in response to the HU-induced anemia. This compensatory increase in JAK/STAT signaling may counteract the beneficial effects of cytoreduction at higher doses of HU and represents an adverse effect that should be avoided.

Original languageEnglish (US)
Pages (from-to)1188-1199
Number of pages12
JournalBlood
Volume121
Issue number7
DOIs
StatePublished - Feb 14 2013

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Polycythemia Vera
Hydroxyurea
Alleles
Phenotype
Assays
Spleen
Erythropoiesis
Erythropoietin
Platelets
Granulocytes
Knockout Mice
Anemia
Weight Loss
Animals
Neutrophils
Blood Platelets
Animal Models
Transplantation
Body Weight
Weights and Measures

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kubovcakova, L., Lundberg, P., Grisouard, J., Hao-Shen, H., Romanet, V., Andraos, R., ... Skoda, R. C. (2013). Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. Blood, 121(7), 1188-1199. https://doi.org/10.1182/blood-2012-03-415646

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

In: Blood, Vol. 121, No. 7, 14.02.2013, p. 1188-1199.

Research output: Contribution to journalArticle

Kubovcakova, L, Lundberg, P, Grisouard, J, Hao-Shen, H, Romanet, V, Andraos, R, Murakami, M, Dirnhofer, S, Wagner, KU, Radimerski, T & Skoda, RC 2013, 'Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model', Blood, vol. 121, no. 7, pp. 1188-1199. https://doi.org/10.1182/blood-2012-03-415646
Kubovcakova, Lucia ; Lundberg, Pontus ; Grisouard, Jean ; Hao-Shen, Hui ; Romanet, Vincent ; Andraos, Rita ; Murakami, Masato ; Dirnhofer, Stephan ; Wagner, Kay Uwe ; Radimerski, Thomas ; Skoda, Radek C. / Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model. In: Blood. 2013 ; Vol. 121, No. 7. pp. 1188-1199.
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