Myelofibrosis biology and contemporary management.

ABSTRACT

Myelofibrosis is an enigmatic myeloproliferative neoplasm, despite noteworthy strides in understanding its genetic underpinnings. Driver mutations involving JAK2, CALR or MPL in 90% of patients mediate constitutive JAK-STAT signaling which, in concert with epigenetic alterations (ASXL1, DNMT3A, SRSF2, EZH2, IDH1/2 mutations), play a fundamental role in disease pathogenesis. Aberrant immature megakaryocytes are a quintessential feature, exhibiting reduced GATA1 protein expression and secreting a plethora of pro-inflammatory cytokines (IL-1 ß, TGF-ß), growth factors (b-FGF, PDGF, VEGF) in addition to extra cellular matrix components (fibronectin, laminin, collagens). The ensuing disrupted interactions amongst the megakaryocytes, osteoblasts, endothelium, stromal cells and myofibroblasts within the bone marrow culminate in the development of fibrosis and osteosclerosis. Presently, prognostic assessment tools for primary myelofibrosis (PMF) are centered on genetics, with incorporation of cytogenetic and molecular information into the mutation-enhanced (MIPSS 70-plus version 2.0) and genetically-inspired (GIPSS) prognostic scoring systems. Both models illustrate substantial clinical heterogeneity in PMF and serve as the crux for risk-adapted therapeutic decisions. A major challenge remains the dearth of disease-modifying drugs, whereas allogeneic transplant offers the chance of long-term remission for some patients. Our review serves to synopsise current appreciation of the pathogenesis of myelofibrosis together with emerging management strategies.