AUTHOR=Fulvio Giovanni , Baldini Chiara , Mosca Marta , di Paolo Antonello , Bocci Guido , Palumbo Giuseppe Alberto , Cacciola Emma , Migliorini Paola , Cacciola Rossella , Galimberti Sara 

TITLE=Philadelphia chromosome-negative myeloproliferative chronic neoplasms: is clonal hematopoiesis the main determinant of autoimmune and cardio-vascular manifestations?

JOURNAL=Frontiers in Medicine

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1254868

DOI=10.3389/fmed.2023.1254868

ISSN=2296-858X

ABSTRACT=In this article we reviewed the possible mechanisms linking the clonal hematopoiesis of indeterminate potential (CHIP) to chronic myeloproliferative neoplasms (MPNs), autoimmune diseases (ADs) and cardiovascular manifestations (CADs). CHIP means the presence of clonal mutations with an allelic frequency >2% in the peripheral blood without dysplasia, overt hematological neoplasias or blood cells count abnormalities, and characterizes up to 20% of elderly healthy people, representing a risk factor for myelodysplastic neoplasms and acute leukemia. In MPNs, CHIP is frequently represented by the JAK2V617F or DNMT3A, TET2, or ASXL1 mutationsthat have a 12 and 1.7-2-fold increase in CADs, respectively. Specifically, JAK2-mutated cells produce excessive cytokines and reactive oxygen species leading to pro-inflammatory modifications in the bone marrow microenvironment; as a consequence, the likelihood of experiencing thrombosis is influenced by the variant allele frequency (VAF) of the JAK2V617F mutation that seems to be also correlated with anti-endothelial cell antibodies that sustains thrombosis. On the other hand, DNMT3A mutations induce pro-inflammatory T-cell polarization and activate the inflammasome complex, while TET2 downregulation leads to endothelial cell autophagy and inflammatory factors upregulation. As result, in patients with TET2 and DNMT3Arelated CHIP, the inflammasome hyperactivation represents a potential cause of CADs.CHIP is also present in giant and small vessel vasculitis, which the ADs more frequently associated with MPNs. In these diseases, it is well known the prominent role of monocytes and of neutrophils in the Neutrophil Extracellular Traps (NET) formation in addition to anti-endothelial cell antibodies, with a final procoagulant effect. ADs such as systemic lupus erythematosus, psoriasis, and arthritis, are also characterised by an overexpression of the Rho-associated coiled-coil containing protein kinase 2 (ROCK2), a serine/threonine kinase that can hyper-activate the JAK-STAT pathway. Interestingly, hyper-activation of ROCK2 has also been observed in myeloid malignancies, where it promotes the growth and survival of leukemic cells.In summary, the presence of CHIP, with or without neoplasia, can be associated with autoimmune manifestations and thrombosis. In the presence of these manifestations, it seems necessary a "diseasemodifying therapy" that may reduce the clonal burden or inhibit the clonally activated JAK pathway.