Myeloproliferative neoplasms (MPN) are chronic myeloid malignancies characterized by constitutive activation of JAK2 signaling. Clinical JAK2 inhibitors bring important benefits for patients, but have limited disease-modifying activity. Allogeneic hematopoietic cell transplantation remains the only curative treatment to date.
The Meyer lab has a specific interest in the oncogenic signaling pathways driving MPN. We have demonstrated that activation of the MAPK pathway, involving MEK1/2 and ERK1/2 kinases and implicated in several cancers, limits JAK2 inhibitor therapy and needs to be addressed to enhance efficacy (Stivala, JCI 2019; Brkic, Leukemia 2021). Building on this work, we are investigating SHP2 as a signaling node linking oncogenic JAK2 activity to MAPK pathway activation and as a potential therapeutic vulnerability in MPN (manuscript in preparation). These findings have translated into the ADORE clinical study (NCT04097821). A phase 1/2a investigator initiated trial (IIT) on combined JAK2 and MEK inhibition in pre-transplant patients is currently being initiated at University Hospitals Bern (Inselspital) and Basel (USB).
Our lab is investigating mechanisms of resistance that mediate loss of response to clinical JAK2 inhibitors, as well as approaches to overcome resistance (Meyer, Cancer Cell 2015; Codilupi, CCR 2024). We study primary MPN patient cells using multi-omics approaches, and transgenic mouse and cell-based models. Notably, we are involved in the characterization of novel types of JAK2 inhibitors, including type II JAK2 inhibitors currently in development towards clinical studies (Usart, Meyer et al, Blood 2025).
