JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice

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 m...

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Main Authors:	Debeurme, Franck, Lacout, Catherine, Moratal, Claudine, Bagley, Rebecca G, Vainchenker, William, Adrian, Francisco, Villeval, Jean-Luc
Format:	Online
Language:	English
Published:	John Wiley & Sons, Ltd 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627562/

id	pubmed-4627562
recordtype	oai_dc
spelling	pubmed-46275622015-11-05 JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice Debeurme, Franck Lacout, Catherine Moratal, Claudine Bagley, Rebecca G Vainchenker, William Adrian, Francisco Villeval, Jean-Luc Original Articles 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 JAK2V617F 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 JAK2V617F 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. John Wiley & Sons, Ltd 2015-11 2015-07-14 /pmc/articles/PMC4627562/ /pubmed/26176817 http://dx.doi.org/10.1111/jcmm.12608 Text en © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Debeurme, Franck Lacout, Catherine Moratal, Claudine Bagley, Rebecca G Vainchenker, William Adrian, Francisco Villeval, Jean-Luc
spellingShingle	Debeurme, Franck Lacout, Catherine Moratal, Claudine Bagley, Rebecca G Vainchenker, William Adrian, Francisco Villeval, Jean-Luc JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice
author_facet	Debeurme, Franck Lacout, Catherine Moratal, Claudine Bagley, Rebecca G Vainchenker, William Adrian, Francisco Villeval, Jean-Luc
author_sort	Debeurme, Franck
title	JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice
title_short	JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice
title_full	JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice
title_fullStr	JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice
title_full_unstemmed	JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice
title_sort	jak2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice
description	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 JAK2V617F 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 JAK2V617F 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.
publisher	John Wiley & Sons, Ltd
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627562/
_version_	1613495412148142080

JAK2 inhibition has different therapeutic effects according to myeloproliferative neoplasm development in mice

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