Investigation of cellular and molecular effects of metformin treatment in rare myeloid neoplasms

Abstract

Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS) / myeloproliferative neoplasm (MPN) unclassified are rare myeloid neoplasms with overlapping laboratory and molecular characteristics, challenging the differential diagnosis and the development of therapies. Mutations in the CSF3R gene, which encodes the granulocyte colony stimulating factor receptor (G-CSFR), occur in CNL and aCML and result in the activation of JAK/STAT, PI3K/AKT/mTOR and MAPK signaling pathways. Metformin has been associated with an antitumor activity, including hematological malignancies. We have recently identified metformin as having anti-neoplastic effects in vitro and in vivo, through mechanisms including inhibition of JAK/STAT and oxidative mitochondrial function. The aims of this project will be to evaluate the cellular and molecular effects of metformin in rare myeloid neoplasms, especially those with CSF3R mutation with JAK/STAT activation. The in vitro metformin effect will be evaluated on colony formation, mitochondrial activity, expression and protein activation, proliferation, apoptosis and cell cycle in primary cells of patients with rare myeloid neoplasms and in Ba/F3 cell line transduced to express CSF3R T618I. The in vivo effect of metformin will be evaluated on disease burden and survival of the murine model of CNL induced by the CSF3R T618I mutation and on the self-renewal capacity of the hematopoietic stem cell in a humanized murine model. (AU)