Abstract
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.