Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Abstract

Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.

Keywords: clonal hematopoiesis; cytokines; inflammation; megakaryocytes; mutations; myeloproliferative neoplasms; polymorphisms.

Figure 1

Elements contributing to onco-inflammation in MPNs. The chronic inflammatory state in MPNs is determined by (i) inherited genetic variants of the host; (ii) acquired somatic mutations leading to a premalignant condition (clonal hematopoiesis) first and then to malignant clone expansion; (iii) ILs, growth factors, chemokines, NOS, and ROS released both at a local and a systemic level; (iv) tumor microenvironment (bone marrow immune, stromal, and endothelial cells). All these elements act in turn on the MPN clone eliciting its transformation into a more aggressive disease (sMF or/and blast phase). ILs: interleukins; NOS: Nitric Oxide Species; ROS: Reactive Oxygen Species; sMF: secondary Myelofibrosis.