The Genetic Basis of Primary Myelofibrosis and Its Clinical Relevance

Abstract

Among classical BCR-ABL-negative myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF) is the most aggressive subtype from a clinical standpoint, posing a great challenge to clinicians. Whilst the biological consequences of the three MPN driver gene mutations (JAK2, CALR, and MPL) have been well described, recent data has shed light on the complex and dynamic structure of PMF, that involves competing disease subclones, sequentially acquired genomic events, mostly in genes that are recurrently mutated in several myeloid neoplasms and in clonal hematopoiesis, and biological interactions between clonal hematopoietic stem cells and abnormal bone marrow niches. These observations may contribute to explain the wide heterogeneity in patients’ clinical presentation and prognosis, and support the recent effort to include molecular information in prognostic scoring systems used for therapeutic decision-making, leading to promising clinical translation. In this review, we aim to address the topic of PMF molecular genetics, focusing on four questions: (1) what is the role of mutations on disease pathogenesis? (2) what is their impact on patients’ clinical phenotype? (3) how do we integrate gene mutations in the risk stratification process? (4) how do we take advantage of molecular genetics when it comes to treatment decisions?

VEGFA rs3025020 Polymorphism Contributes to CALR-Mutation Susceptibility and Is Associated with Low Risk of Deep Vein Thrombosis in Primary Myelofibrosis

“…With the Fine and Gray model, with thrombotic event of interest and overall mortality of the competing risk, the cumulative incidence of deep vein thrombosis in typical sites at the end of follow-up was 6.7% (95% CI, 3.1, 12.2) (►Fig. 1). When refining the assessment of VEGFA rs3025020 status for the risk of thrombosis, we showed an increase in risk for CC genotype with respect to CT/TT genotype, with sHR for CT/TT 0.37 (0.14, 0.95) p ¼ 0.039.…”

“…Primary myelofibrosis (PMF) is a myeloproliferative disorder mostly caused by gain-of-function driver mutations in Janus kinase-2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus (MPL). 1 Persons with these mutations often have additional variations in ASXL1, EZH2, DMNT3A, IDH1, and IDH2. 2 However, the mutation topography of PMF does not completely account for the different phenotypes including clinical and laboratory co-variates and risks of thrombosis, progression, and transformation to acute myeloid leukemia.…”

Severe ARDS due to Ruxolitinib discontinuation syndrome: case presentation and literature review

“…PMF usually presents with symptomatic splenomegaly, debilitating systemic symptoms and cytopenia in differing degrees, and is associated with reduced life expectancy. Treatment options for myelofibrosis include stem cell transplantation, JAK inhibitors and supportive therapy (including hydroxyurea) [ 9 ].…”

The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: “Crafting” a Microenvironment That Matters

“…TN MF is associated with an aggressive clinical behavior characterized by a higher risk of developing anemia and thrombocytopenia, poorer outcomes in comparison with patients affected by the other MF molecular subtypes and a high rate of leukemic transformation. The molecular basis of TN remains mostly unknown, although a high molecular complexity has been previously described and rare, alternative, somatic mutations in both JAK2 exon 14 and MPL exon 10 have been previously described [ 117 , 118 , 119 ]. Beyond the molecular pathogenesis, chronic inflammation with abnormal release of pro-inflammatory cytokines has been indicated as main contributor in MF initiation/clonal evolution.…”