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Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy

Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mecha...

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Autores principales: Treliński, Jacek, Chojnowski, Krzysztof, Cebula-Obrzut, Barbara, Smolewski, Piotr
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466431/
https://www.ncbi.nlm.nih.gov/pubmed/22418850
http://dx.doi.org/10.1007/s12032-012-0202-3
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author Treliński, Jacek
Chojnowski, Krzysztof
Cebula-Obrzut, Barbara
Smolewski, Piotr
author_facet Treliński, Jacek
Chojnowski, Krzysztof
Cebula-Obrzut, Barbara
Smolewski, Piotr
author_sort Treliński, Jacek
collection PubMed
description Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mechanisms can be deregulation of apoptosis, resulting in accumulation of bone marrow MKCs. In this study, we investigated the apoptotic profile, as well as the expression of apoptosis-regulating protein in MKCs and bone marrow mononuclear cells (BMMCs) in 43 patients with ET. We found significantly lower percentages of apoptotic MKCs and BMMCs, as measured by the rate of annexin-V+ and caspase-3+ (Cas-3+) cells in relation to healthy volunteers. Additionally, the expression of Bax protein in ET patients naïve to cytoreductive treatment, as well as their Bax/Bcl-2 ratio, was significantly lower than in controls (p = <0.05 and p < 0.001, respectively). Patients positive for the JAK2V617F mutation had markedly higher activation of Cas-3, as well as higher Bax expression (p = 0.02 and p = 0.04, respectively) than JAK2V617F negative cases. There were no marked differences between patients already treated with anagrelide (ANA) or hydroxyurea (HU), although tendency toward the higher apoptosis rate was observed in the HU-treated group. In conclusion, these results demonstrate the inhibition of caspase-dependent apoptosis of both MKCs and BMMCs in untreated ET. This is associated with upregulation of Bcl-2 and downregulation of Bax proteins, predominantly in JAK2V617F negative cases. Patients treated with HU showed slightly higher pro-apoptotic Bax/Bcl-2 index than patients on ANA therapy, which may influence the better efficacy of HU therapy in ET.
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spelling pubmed-34664312012-10-11 Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy Treliński, Jacek Chojnowski, Krzysztof Cebula-Obrzut, Barbara Smolewski, Piotr Med Oncol Original Paper Essential thrombocythemia (ET) is a clonal myeloproliferative disorder characterized by overproduction of megakaryocytes (MKCs) and platelets. The recent discovery of the JAK2 mutation has shed a new light on the development of ET but its pathogenesis still remains unknown. One of the possible mechanisms can be deregulation of apoptosis, resulting in accumulation of bone marrow MKCs. In this study, we investigated the apoptotic profile, as well as the expression of apoptosis-regulating protein in MKCs and bone marrow mononuclear cells (BMMCs) in 43 patients with ET. We found significantly lower percentages of apoptotic MKCs and BMMCs, as measured by the rate of annexin-V+ and caspase-3+ (Cas-3+) cells in relation to healthy volunteers. Additionally, the expression of Bax protein in ET patients naïve to cytoreductive treatment, as well as their Bax/Bcl-2 ratio, was significantly lower than in controls (p = <0.05 and p < 0.001, respectively). Patients positive for the JAK2V617F mutation had markedly higher activation of Cas-3, as well as higher Bax expression (p = 0.02 and p = 0.04, respectively) than JAK2V617F negative cases. There were no marked differences between patients already treated with anagrelide (ANA) or hydroxyurea (HU), although tendency toward the higher apoptosis rate was observed in the HU-treated group. In conclusion, these results demonstrate the inhibition of caspase-dependent apoptosis of both MKCs and BMMCs in untreated ET. This is associated with upregulation of Bcl-2 and downregulation of Bax proteins, predominantly in JAK2V617F negative cases. Patients treated with HU showed slightly higher pro-apoptotic Bax/Bcl-2 index than patients on ANA therapy, which may influence the better efficacy of HU therapy in ET. Springer US 2012-03-15 2012 /pmc/articles/PMC3466431/ /pubmed/22418850 http://dx.doi.org/10.1007/s12032-012-0202-3 Text en © The Author(s) 2012 https://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Original Paper
Treliński, Jacek
Chojnowski, Krzysztof
Cebula-Obrzut, Barbara
Smolewski, Piotr
Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy
title Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy
title_full Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy
title_fullStr Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy
title_full_unstemmed Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy
title_short Impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with JAK2V617F mutational status and cytoreductive therapy
title_sort impaired apoptosis of megakaryocytes and bone marrow mononuclear cells in essential thrombocythemia: correlation with jak2v617f mutational status and cytoreductive therapy
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466431/
https://www.ncbi.nlm.nih.gov/pubmed/22418850
http://dx.doi.org/10.1007/s12032-012-0202-3
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