Revisiting Circulating Extracellular Matrix Fragments as Disease Markers in Myelofibrosis and Related Neoplasms

SIMPLE SUMMARY: MPN blood cancers are characterized by elevated blood cell counts. Chronic inflammation drives MPNs, which after 10–30 years, may lead to bone marrow failure due to replacement of bone marrow by connective tissue. Chronic inflammation also impacts other organs causing impaired vision, osteoporosis, fractures, heart failure and decreased lung and kidney function. MPNs are also associated with an increased risk of other cancers. Novel, noninvasive technologies are needed to improve the early detection of fibrosis development and MPN progression and to monitor the efficacy of treatment. Herein, we review current knowledge and focus on novel technologies for the measurement of circulating connective tissue biomarkers in MPNs. Future research directions are provided, suggesting studies on single markers or combinations before and during treatment with old and new agents, both targeting the diseased bone marrow cells and the inflammatory processes that drive the progressive fibrosis, which if left untreated, may ultimately lead to bone marrow failure or leukemic transformation. ABSTRACT: Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10–30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation—“a wound that never heals”—we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs.