Linezolid Acts as a Selective Inhibitor of the JAK2 V617F Mutation.

UNLABELLED: The JAK2 V617F (JAK2 VF ) driver mutation is found in 95% of patients with polycythemia vera (PV), a progressive myeloproliferative neoplasm. Current treatments suppress excessive hematopoiesis but lack specificity for targeting JAK2 VF cells, are unable to deplete mutant stem/progenitor cells and ultimately result in drug resistance. We discovered that the FDA-approved antibiotic, linezolid (LZD), ameliorates the PV phenotype across multiple model systems. LZD suppressed cell proliferation and STAT5 signaling, altered the cell cycle, and increased apoptosis of JAK2 VF -harboring human erythroleukemia cells, but not in wild-type acute leukemia cells. Computational modelling indicated that LZD interacts specifically with mutant JAK2 VF but not with wild-type JAK2 protein. We further showed that, in JAK2 VF mice that faithfully recapitulate human PV, LZD mitigates disease burden by selectively targeting JAK2 VF stem cells thereby normalizing spleen size and blood counts. LZD also inhibited hematopoietic colony formation by patient-derived peripheral blood mononuclear cells, with the more primitive progenitors being preferred targets. Importantly, LZD selectively decreased JAK2 VF+ colony numbers, without impacting wild-type JAK2 colonies. In all, the data provide a firm foundation for evaluating LZD-like molecules as an effective therapy for PV and other myeloproliferative neoplasms.

KEY POINTS: Linezolid acts as a JAK2 V617F IZselective inhibitor in PV mouse models and PV patient samples while sparing wildIZtype hematopoiesis. Linezolid acts directly on JAK2 V617F hematopoietic stem cells.