Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR-ABL-Negative Myeloproliferative Neoplasm

Abstract

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In BCR-ABL1-negative MPNs, the driver mutations include JAK 2, MPL, and CALR. Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.

Keywords: ROS; driver mutation; essential thrombocythemia; inflammation; myelofibrosis; myeloproliferative neoplasms; oxidative stress; polycythemia vera; thrombotic complication.

Figure 1

Effect of LCN2 on the growth of myelofibrosis (MF) hematopoietic stem cells. LCN2 fosters the growth of splenic endothelial cells, causing the enhanced production of IL-8 by splenic stromal cells. Such an increase plays a role in the formation of an endothelial cell niche, which, in turn, promotes the growth of myelofibrosis hematopoietic stem cells.

Figure 2

Oxidative stress, the NF-κB pathway, and the JAK–STAT pathway. Oxidative stress stimulates the NF-κB pathway, fostering a cycle in which oxidative stress generates ROS, which, in turn, produces more oxidative stress (left). However, inflammatory mediators stimulate the Suppressors of cytokine signaling (SOCS), in turn linking to JAKs, interrupting the JAK–STAT pathway (right) and, ultimately, blocking the inflammatory process.