Mutations, inflammation and phenotype of myeloproliferative neoplasms

Abstract

Knowledge on the myeloproliferative neoplasms (MPNs) - polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) - has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: JAK2V617F, observed in PV, ET and PMF; and the MPL and CALR mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations (ASXL1, DNMT3A, TET2, others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies.

Keywords: essential thrombocythemia inflammation; mutations; myeloproliferative neoplasms (MPN); polycythemia vera; primary fibrosis (PMF); therapeutic targets.

Figure 1

Representation of the pathogenesis of MPNs, associated mutations and inflammation, and impact on MPN phenotype. Part (A) JAK2V617F-mutant allele burdens in the different MPN phenotypes. Patients diagnosed with classic MPNs (PV, ET, PMF) or with refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) or splanchnic vein thrombosis (SVT) can present with 25-50% JAK2V617F-mutated alleles in blood cells. The size of JAK2V617F-mutated clones varies: MPN clones are typically heterozygous for the JAK2V617F mutation in ET and RARS-T, and homozygous in PV and PMF. Note that in PV and in PMF with <50% JAK2V617F, clones may be heterozygous or homozygous for JAK2V617F. Part (B) Pathogenesis of MPNs and impact on MPN phenotype. Chronic inflammation of various causes (smoking, inflammatory diseases, auto-immunity, high-fat diet, metabolism disorders, genetic pre-disposition to inflammation) leads to chronic activation of the NF-κB and JAK/STAT pathways, hereby further increasing the production of inflammatory cytokines and myeloid cells, and facilitating the acquisition of non-driving, concomitant mutations (in the DNMT3A, TET2, SRSF2, SF3B1 genes) as well as driving JAK/STAT-activating mutations (in the JAK2, CALR or MPL genes) in myeloid progenitors, resulting in the development of a MPN. The MPN phenotype (ET, PV, PMF, RARS-T) depends in part from the driving JAK2, CALR or MPL mutation(s) and the presence of concomitant mutation(s), and in part from the level and type of inflammation, iron stocks, and metabolism. The mutation-dependent production of cytokines is indicated by thin arrows and + signs. Concomitant mutations can be found in all MPN phenotypes but are more frequent in PMF, which is indicated by arrows. The ┬ symbols indicate the different targets potentially useful in MPN prevention and therapy. (*) In case of inflammation and iron deficit.