Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia

Abstract A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on JAK2, MPL, and CALR and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a...

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Autores principales:	Tadaaki Inano, Marito Araki, Soji Morishita, Misa Imai, Yoshihiko Kihara, Maho Okuda, Yinjie Yang, Masafumi Ito, Satoshi Osaga, Hiroyuki Mano, Yoko Edahiro, Tomonori Ochiai, Kyohei Misawa, Yasutaka Fukuda, Jun Ando, Norio Komatsu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a94cc6fdb69b4023a4cc0476b24bda89
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spelling	oai:doaj.org-article:a94cc6fdb69b4023a4cc0476b24bda892021-12-02T17:19:16ZCell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia10.1038/s41598-021-97106-92045-2322https://doaj.org/article/a94cc6fdb69b4023a4cc0476b24bda892021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97106-9https://doaj.org/toc/2045-2322Abstract A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on JAK2, MPL, and CALR and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a single institution, centrally reviewed bone marrow specimens, and identified 23 TN-ET patients. Analysis of clinical records revealed that TN-ET patients were mostly young female, without a history of thrombosis or progression to secondary myelofibrosis and leukemia. Sequencing analysis and human androgen receptor assays revealed that the majority of TN-ET patients exhibited polyclonal hematopoiesis, suggesting a possibility of reactive thrombocytosis in TN-ET. However, the serum levels of thrombopoietin (TPO) and interleukin-6 in TN-ET patients were not significantly different from those in ET patients with canonical mutations and healthy individuals. Rather, CD34-positive cells from TN-ET patients showed a capacity to form megakaryocytic colonies, even in the absence of TPO. No signs of thrombocytosis were observed before TN-ET development, denying the possibility of hereditary thrombocytosis in TN-ET. Overall, these findings indicate that TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and is paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis.Tadaaki InanoMarito ArakiSoji MorishitaMisa ImaiYoshihiko KiharaMaho OkudaYinjie YangMasafumi ItoSatoshi OsagaHiroyuki ManoYoko EdahiroTomonori OchiaiKyohei MisawaYasutaka FukudaJun AndoNorio KomatsuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tadaaki Inano Marito Araki Soji Morishita Misa Imai Yoshihiko Kihara Maho Okuda Yinjie Yang Masafumi Ito Satoshi Osaga Hiroyuki Mano Yoko Edahiro Tomonori Ochiai Kyohei Misawa Yasutaka Fukuda Jun Ando Norio Komatsu Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia
description	Abstract A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on JAK2, MPL, and CALR and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a single institution, centrally reviewed bone marrow specimens, and identified 23 TN-ET patients. Analysis of clinical records revealed that TN-ET patients were mostly young female, without a history of thrombosis or progression to secondary myelofibrosis and leukemia. Sequencing analysis and human androgen receptor assays revealed that the majority of TN-ET patients exhibited polyclonal hematopoiesis, suggesting a possibility of reactive thrombocytosis in TN-ET. However, the serum levels of thrombopoietin (TPO) and interleukin-6 in TN-ET patients were not significantly different from those in ET patients with canonical mutations and healthy individuals. Rather, CD34-positive cells from TN-ET patients showed a capacity to form megakaryocytic colonies, even in the absence of TPO. No signs of thrombocytosis were observed before TN-ET development, denying the possibility of hereditary thrombocytosis in TN-ET. Overall, these findings indicate that TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and is paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis.
format	article
author	Tadaaki Inano Marito Araki Soji Morishita Misa Imai Yoshihiko Kihara Maho Okuda Yinjie Yang Masafumi Ito Satoshi Osaga Hiroyuki Mano Yoko Edahiro Tomonori Ochiai Kyohei Misawa Yasutaka Fukuda Jun Ando Norio Komatsu
author_facet	Tadaaki Inano Marito Araki Soji Morishita Misa Imai Yoshihiko Kihara Maho Okuda Yinjie Yang Masafumi Ito Satoshi Osaga Hiroyuki Mano Yoko Edahiro Tomonori Ochiai Kyohei Misawa Yasutaka Fukuda Jun Ando Norio Komatsu
author_sort	Tadaaki Inano
title	Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia
title_short	Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia
title_full	Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia
title_fullStr	Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia
title_full_unstemmed	Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia
title_sort	cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a94cc6fdb69b4023a4cc0476b24bda89
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Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia

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