IDH2 mutation accelerates TPO-induced myelofibrosis with enhanced S100a8/a9 and NFκB signaling in vivo.

Autor: Lin CC; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan.; Division of Hematology Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan.; Graduate Institute of Clinical Medicine, College of Medicine National Taiwan University Taipei Taiwan., Yao CY; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan.; Division of Hematology Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan., Wang YH; Division of Hematology Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan., Hsu YC; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan., Yuan CT; Graduate Institute of Clinical Medicine, College of Medicine National Taiwan University Taipei Taiwan.; Department of Pathology Graduate Institute of Oncology College of Medicine National Taiwan University Taipei Taiwan.; Department of Pathology National Taiwan University Cancer Center Taipei Taiwan., Chen TC; Graduate Institute of Clinical Medicine, College of Medicine National Taiwan University Taipei Taiwan.; Division of Hematology and Medical Oncology Department of Internal Medicine Taichung Veterans General Hospital Taipei Taiwan., Hsu CL; Department of Medical Research National Taiwan University Cancer Center Taipei Taiwan., Lee SH; Division of Cellular Therapy Department of Integrated Diagnostics and Therapeutics National Taiwan University Hospital Taipei Taiwan., Lee JY; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan., Shih PT; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan., Kao CJ; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan., Chuang PH; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan., Kuo YY; Tai-Cheng Stem Cell Therapy Center National Taiwan University Taipei Taiwan., Hou HA; Division of Hematology Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan., Chou WC; Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan.; Division of Hematology Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan., Tien HF; Division of Hematology Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan.; Division of Hematology and Medical Oncology Department of Internal Medicine Far Eastern Memorial Hospital New Taipei Taiwan.
Jazyk: angličtina
Zdroj: EJHaem [EJHaem] 2024 Jul 28; Vol. 5 (4), pp. 738-748. Date of Electronic Publication: 2024 Jul 28 (Print Publication: 2024).
DOI: 10.1002/jha2.983
Abstrakt: Introduction: IDH2 mutation is an unfavorable prognostic factor in patients with primary myelofibrosis (PMF) but its effect on myelofibrosis (MF) remains largely unclear.
Methods: In this study, we aimed to elucidate the roles of IDH2 mutation in the development and progression of MF by transcriptomic and molecular techniques using the Idh2 R172K transgenic mice.
Results: We found that thrombopoietin (TPO)-overexpressed Idh2 R172K ( Idh2 R172K + TPO) mice had accelerated progression to MF, compared with TPO-overexpressed Idh2- wild (WT + TPO) mice, showing activation of multiple inflammatory pathways, among which nuclear factor κB (NFκB) was the most significantly enhanced. Single-cell transcriptomes of the marrow cells in early MF showed that S100a8/a9 expression was mainly confined to neutrophil progenitors in the WT + TPO mice, but highly expressed in several types of myeloid precursor cells, including the megakaryocyte progenitors in the Idh2 R172K + TPO group. Furthermore, Idh2 R172K mice at age of 18 months had larger spleens, increased S100a8/a9-Tlr4 expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with IDH2 mutations had higher bone marrow plasma S100A8/A9 levels than those without IDH2 mutations.
Conclusion: Overall, our findings showed that IDH2 mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in Idh2 R172K + TPO mice.
Competing Interests: The authors declare they have no conflicts of interest.
(© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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