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

Introduction: 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 mutation in the development and progression of MF by transcriptomic and molecular techniques using the transgenic mice.

Results: We found that thrombopoietin (TPO)-overexpressed ( + TPO) mice had accelerated progression to MF, compared with TPO-overexpressed 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 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 + TPO group. Furthermore, mice at age of 18 months had larger spleens, increased expression, and elevated serum S100a8/a9 levels compared with WT mice. PMF patients with mutations had higher bone marrow plasma S100A8/A9 levels than those without mutations.

Conclusion: Overall, our findings showed that mutation induced proinflammatory effects, which further exacerbated MF, as evidenced by the increase in S100a8/a9 levels and NFκB hyperactivation in + TPO mice.