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IDH2 mutation accelerates TPO-induced myelofibrosis with enhanced S100a8/a9 and NFκB signaling in vivo
Chien-Chin Lin1,2,3, Chi-Yuan Yao1,2, Yu-Hung Wang2
1Department of Laboratory Medicine National Taiwan University Hospital Taipei Taiwan.
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.
Insights
Isocitrate dehydrogenase 2 (IDH2) mutations promote inflammation and worsen myelofibrosis (MF) progression. This study reveals IDH2 mutation-induced pro-inflammatory effects, increasing S100a8/a9 levels and NFκB activation in MF.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Isocitrate dehydrogenase 2 (IDH2) mutations are linked to poor prognosis in primary myelofibrosis (PMF).
- The precise role of IDH2 mutations in the development and progression of myelofibrosis (MF) is not fully understood.
Purpose of the Study:
- To investigate the impact of IDH2 mutations on MF development and progression.
- To elucidate the molecular mechanisms underlying IDH2 mutation-driven MF.
Main Methods:
- Utilized Idh2R172K transgenic mice and transcriptomic techniques.
- Analyzed thrombopoietin (TPO)-overexpressed mice with and without Idh2 mutations.
- Performed single-cell transcriptome analysis on bone marrow cells.
Main Results:
- Idh2R172K + TPO mice showed accelerated MF progression compared to WT + TPO mice.
- IDH2 mutation led to hyperactivation of inflammatory pathways, notably nuclear factor κB (NFκB).
- Increased S100a8/a9 expression in myeloid precursors and elevated serum S100a8/a9 levels were observed in Idh2R172K mice and PMF patients with IDH2 mutations.
Conclusions:
- IDH2 mutations induce pro-inflammatory effects, exacerbating MF.
- Elevated S100a8/a9 levels and NFκB hyperactivation are key mechanisms in IDH2 mutation-driven MF.
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