Study of the mechanisms of CC Chemokine Receptor type 2 (CCR2) overexpression in myelofibrosis: their involvement in CCL2-mediated disease progression and preclinical validation of CCR2 blockade as a new therapeutic strategy

Project objectives

This project aims to identify a new pathogenetic mechanism in the development of myelofibrosis (MF), a myeloploriferative neoplasm which in most cases transforms into leukemia, with a consequent reduction in survival. Indeed, despite significant advances in understanding

of the molecular basis, the pathogenesis of MF still remains unknown. MF is considered the paradigm of inflammation-related cancer development: It is emerging from published work chiaramind, in fact, that while the onset of the disease is caused by acquired somatic mutations of myeloid target genes, its progression is driven, at least in part, by inflammation. CCL2 is one of the most potent immunomodulatory cytokines known to be elevated in MF patient sera and exerts its effects by preferentially engaging its cognate receptor CCR2. As CCR2 overexpression is emerging as a hallmark feature of MF, in this project we aim to unravel the mechanisms underlying CCR2 overexpression in MF HSC/HPC and explore the therapeutic potential of CCR2 blockade in vitro and in vivo. To this end, we have planned to:

Objective 1: Explore the molecular mechanisms underlying the selective expression of CCR2 in MF HSC/HPC and the role of JAK inhibitor therapy 

Objective 2: preclinically validate, in vitro and in vivo, a new therapeutic strategy in MF based on CCR2 blockade.

The ultimate goal is to identify new pathogenetic mechanisms and provide the preclinical rationale for a new therapy for the treatment of MF.

Start and end date

Project Manager

Coordinating institution of the project

Other institutions involved in the project

• Prof. Elena Maselli, Department of Medicine and Surgery, University of Parma.  
• Higher Institute of Health, Rome Italy

Project funding source