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.

Oxidative Stress in Cancer Cell Metabolism

“…Increased ROS is responsible for the oxidation of negative feedback loop controllers and hence control the actions of other signaling pathways in tumor growth and programmed cell death by the phosphoinositide 3-kinase/protein kinase B (PI3K/PKB) and mitogen-activated protein kinase (MAPK) signaling pathways [ 45 , 46 ] ( Figure 2 ). Reactive oxygen species generation in cancer cells leads to the inactivation of PTEN that leads to an increase in PI3K/Akt signaling that promotes proliferation.…”

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

“…At early stage, the disease may be not clinically apparent and could be described as clonal hematopoiesis with a sub-clinical inflammatory state. The accumulation of ROS in mutated cells damages DNA and favors clonal proliferation, driving disease progression towards full-blown MPN [ 43 , 44 , 45 ]. In particular, JAK2V617F mutation leads to the upregulation of plenty of cytokines, chemokines and growth factors, including interleukins IL-1β, IL-6, IL-8, IL-10, IL-11, IL-12, IL-15, IL-17 and IL-33, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL4, tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), granulocyte macrophage-colony stimulating factor (GM-CSF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and angiopoietin-1, as reported in murine models and in patients’ samples [ 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…The BM niche is essential for sustaining self-renewal of MPN stem cells, hence, providing them with survival advantages over normal HSCs via generation of ROS pro-inflammatory cytokines [ 14 , 302 ]. In view of the positive feedback loop between BM niche and MPN stem cells, various novel agents are developed.…”

“…In addition, disease initiation and progression of Ph-negative MPNs involve the interplay between cell-intrinsic and cell-extrinsic activities. This is characterized by survival advantage of MPN stem cells over normal HSCs that is sustained by a dysregulated bone marrow niche via a positive feedback mechanism [ 9 , 14 ] ( Figure 1 ). Further acquisition of non-driver mutations then plays a pivotal role in determining disease phenotype and promoting leukemic progression [ 9 , 10 , 13 ] ( Figure 2 ).…”