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JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2015 Nov; Vol. 19 (11), pp. 2564-74. Date of Electronic Publication: 2015 Jul 14. - Publication Year :
- 2015
-
Abstract
- JAK2 inhibition therapy is used to treat patients suffering from myeloproliferative neoplasms (MPN). Conflicting data on this therapy are reported possibly linked to the types of inhibitors or disease type. Therefore, we decided to compare in mice the effect of a JAK2 inhibitor, Fedratinib, in MPN models of increasing severity: polycythemia vera (PV), post-PV myelofibrosis (PPMF) and rapid post-essential thrombocythemia MF (PTMF). The models were generated through JAK2 activation by the JAK2(V617F) mutation or MPL constant stimulation. JAK2 inhibition induced a correction of splenomegaly, leucocytosis and microcytosis in all three MPN models. However, the effects on fibrosis, osteosclerosis, granulocytosis, erythropoiesis or platelet counts varied according to the disease severity stage. Strikingly, complete blockade of fibrosis and osteosclerosis was observed in the PPMF model, linked to correction of MK hyper/dysplasia, but not in the PTMF model, suggesting that MF development may also become JAK2-independent. Interestingly, we originally found a decreased in the JAK2(V617F) allele burden in progenitor cells from the spleen but not in other cell types. Overall, this study shows that JAK2 inhibition has different effects according to disease phenotypes and can (i) normalize platelet counts, (ii) prevent the development of marrow fibrosis/osteosclerosis at an early stage and (iii) reduce splenomegaly through blockage of stem cell mobilization in the spleen.<br /> (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Subjects :
- Animals
Disease Progression
Mice
Platelet Count
Polycythemia Vera blood
Polycythemia Vera physiopathology
Primary Myelofibrosis blood
Primary Myelofibrosis physiopathology
Splenomegaly drug therapy
Thrombocythemia, Essential blood
Thrombocythemia, Essential physiopathology
Janus Kinase 2 antagonists & inhibitors
Polycythemia Vera drug therapy
Primary Myelofibrosis drug therapy
Protein Kinase Inhibitors administration & dosage
Pyrrolidines administration & dosage
Sulfonamides administration & dosage
Thrombocythemia, Essential drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 19
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 26176817
- Full Text :
- https://doi.org/10.1111/jcmm.12608