pevnev, G. | bioRxiv Science

bioRxiv2026

Linezolid Acts as a Selective Inhibitor of the JAK2V617F Mutation

The JAK2V617F (JAK2VF) 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 JAK2VF 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 JAK2VF-harboring human erythroleukemia cells, but not in wild-type acute leukemia cells. Computational modelling indicated that LZD interacts specifically with mutant JAK2VF but not with wild-type JAK2 protein. We further showed that, in JAK2VF mice that faithfully recapitulate human PV, LZD mitigates disease burden by selectively targeting JAK2VF 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 JAK2VF+ 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 pointsO_LILinezolid acts as a JAK2V617FIZselective inhibitor in PV mouse models and PV patient samples while sparing wildIZtype hematopoiesis. C_LIO_LILinezolid acts directly on JAK2V617F hematopoietic stem cells. C_LI

cancer biology↗

bioRxiv2026

Erythroferrone Modulates Osteoblast-Osteoclast Crosstalk During Bone Remodeling

Erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. Recent evidence demonstrates that ERFE is also expressed in osteoblasts and osteoclasts and Erfe-/- mice display low-bone-mass arising from increased bone resorption despite a concomitant increase in bone formation. To mechanistically dissect how bone-derived ERFE exerts an osteoprotective effect, we first created Erfefl/fl mice, which were then crossed with Col2.3-Cre mice to generate osteoblast-selective Erfe mutants (or Erfefl/fl;Col2.3-Cre mice). We now demonstrate that ERFE derived from osteoblasts is not responsible for the decreased BMD noted in Erfe-/- mice, revealing enhanced BMD during anabolic stress in Erfefl/fl;Col2.3-Cre mice. Consistently, in contrast to global ERFE loss, osteoblast-selective ERFE loss does not increase osteoclasts in vivo. Furthermore, our results demonstrate that ERFE loss in osteoblasts induces osteoclast Erfe expression in co-culture experiments in vitro. Finally, the osteoclastogenesis gene program is induced in co-culture with osteoblasts only when ERFE is lost in osteoclasts. Taken together, our finding provide strong evidence of osteoclast-derived ERFE as a central osteoprotective regulator of bone mass, its loss resulting in net bone loss in Erfe-/- mice. BRIEF SUMMARYLoss of erythroferrone derived from osteoclasts enhances osteoclastogenesis resulting in accelerated bone loss. SIGNIFICANCE STATEMENTCanonical erythroferrone (ERFE) function includes hepcidin suppression through bone morphogenic proteins (BMPs) sequestration, establishing the rationale for ERFE-mediated regulation of bone homeostasis. We previously showed that global ERFE loss controls bone mass. Here, we report that osteoclast-derived ERFE is a major regulator of osteoclastogenesis. For this, we crossed Erfefl/fl with Col2.3-Cre mice to generate osteoblast-selective Erfe mutants, demonstrating that osteoblast-derived ERFE does not recapitulate bone loss found in global ERFE knockout mice. In contrast, bone mineral density is enhanced during anabolic stress in Erfefl/fl;Col2.3-Cre mice. Finally, we document that osteoclast ERFE loss enhances osteoclastogenesis in co-culture with osteoblasts. Together, the data provide compelling evidence that osteoclast-derived ERFE modulates communication between osteoblasts and osteoclasts.

cell biology↗