Proinflammatory phenotype of iPS cell-derived JAK2 V617F megakaryocytes induces fibrosis in 3D in vitro bone marrow niche.

Autor:	Flosdorf N; Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany; Institute for Cell and Tumor Biology, RWTH Aachen University Medical School, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany., Böhnke J; Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany., de Toledo MAS; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany., Lutterbach N; Institute for Cell and Tumor Biology, RWTH Aachen University Medical School, Aachen, Germany., Lerma VG; Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany., Graßhoff M; Institute of Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany., Olschok K; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany., Gupta S; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany., Tharmapalan V; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Institute for Stem Cell Biology, RWTH Aachen University Medical School, Aachen, Germany., Schmitz S; Institute for Cell and Tumor Biology, RWTH Aachen University Medical School, Aachen, Germany., Götz K; Institute for Cell and Tumor Biology, RWTH Aachen University Medical School, Aachen, Germany., Schüler HM; Institute for Human Genetics and Genome Medicine, Faculty of Medicine, RWTH Aachen University, Aachen, Germany; Center for Rare Diseases, Medical Faculty, and University Hospital Düsseldorf Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany., Maurer A; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany., Sontag S; Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany., Küstermann C; Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany., Seré K; Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany; Institute for Cell and Tumor Biology, RWTH Aachen University Medical School, Aachen, Germany., Wagner W; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Institute for Stem Cell Biology, RWTH Aachen University Medical School, Aachen, Germany., Costa IG; Institute of Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany., Brümmendorf TH; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany., Koschmieder S; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany., Chatain N; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany., Castilho M; Eindhoven University of Technology, Eindhoven, the Netherlands., Schneider RK; Institute for Cell and Tumor Biology, RWTH Aachen University Medical School, Aachen, Germany., Zenke M; Department of Cell Biology, Institute for Biomedical Engineering, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany. Electronic address: martin.zenke@rwth-aachen.de.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2024 Feb 13; Vol. 19 (2), pp. 224-238. Date of Electronic Publication: 2024 Jan 25.
DOI:	10.1016/j.stemcr.2023.12.011
Abstrakt:	The myeloproliferative disease polycythemia vera (PV) driven by the JAK2 V617F mutation can transform into myelofibrosis (post-PV-MF). It remains an open question how JAK2 V617F in hematopoietic stem cells induces MF. Megakaryocytes are major players in murine PV models but are difficult to study in the human setting. We generated induced pluripotent stem cells (iPSCs) from JAK2 V617F PV patients and differentiated them into megakaryocytes. In differentiation assays, JAK2 V617F iPSCs recapitulated the pathognomonic skewed megakaryocytic and erythroid differentiation. JAK2 V617F iPSCs had a TPO-independent and increased propensity to differentiate into megakaryocytes. RNA sequencing of JAK2 V617F iPSC-derived megakaryocytes reflected a proinflammatory, profibrotic phenotype and decreased ribosome biogenesis. In three-dimensional (3D) coculture, JAK2 V617F megakaryocytes induced a profibrotic phenotype through direct cell contact, which was reversed by the JAK2 inhibitor ruxolitinib. The 3D coculture system opens the perspective for further disease modeling and drug discovery. Competing Interests: Declaration of interests W.W. and V.T. are involved in Cygenia GmbH (www.cygenia.com), which provides services for DNA methylation analysis to other scientists. S.K. reports funding from Novartis, Bristol-Myers Squibb, and Janssen/Geron; advisory board honoraria from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI, Roche, Baxalta, GSK, Sierra Oncology, and Sanofi; a patent for Bromodomain and Extra-Terminal (BET) inhibitor at RWTH Aachen University; honoraria from Novartis, Bristol Myers Squibb, Celgene, Geron, Janssen, Pfizer, Incyte, Ariad, Shire, Roche, and AOP Pharma; and other financial support (e.g., travel support) from Alexion, Novartis, Bristol Myers Squibb, Incyte, Ariad, AOP Pharma, Baxalta, CTI, Pfizer, Sanofi, Celgene, Shire, Janssen, Geron, Abbvie, Imago Biosciences, Sierra Oncology, GSK, and Karthos. T.H.B. served as a consultant for Janssen, Merck, Novartis, and Pfizer; received research funding form Novartis and Pfizer; and received honoraria from Janssen, Merck, Novartis, and Pfizer. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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