Dissecting the cellular and molecular effects of metformin in CSF3R T618I myeloproliferative neoplasm

• Grant number: 22/02268-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): August 01, 2022
• Effective date (End): October 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Fabíola Traina
• Grantee: Natasha Peixoto Fonseca
• Supervisor: Jan Jacob Schuringa
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: University Medical Center Groningen (UMCG), Netherlands
• Associated to the scholarship: 19/05722-0 - Investigation of cellular and molecular effects of metformin treatment in rare myeloid neoplasms, BP.DR

Abstract

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative neoplasm (MPN). The overlapping features of CNL with others rare myeloid malignancies, have been 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 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 JAK2 V617F MPN models, through mechanisms including inhibition of JAK/STAT and oxidative mitochondrial function. On this current proposal our aim is to evaluate the cellular and molecular effects of metformin in rare myeloid neoplasms with CSF3R mutation. Our preliminary results demonstrated that metformin treatment in vitro on CSF3R T618I models decreased cell viability and increased apoptosis in a dose- and time-dependent manner by JAK/STAT pathway modulation. In vivo, metformin decreased tumor burden of Ba/F3 CSF3R T618I cells during the first days of treatment but the effect was not sustained. Metformin treatment ex vivo dramatically reduced colony formation of bone marrow and peripheral blood cells from a patient with CNL CSF3R T618I when compared to vehicle. To better understand molecular mechanisms behind metformin treatment, CD34+ cord blood (CB) cells will be transduced to express CSF3R T618I mutation, and then submitted to colony formation and ChIP-seq assays. (AU)