Molecular pathogenesis of the myeloproliferative neoplasms

Abstract

The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Despite distinct clinical entities, these disorders are linked by morphological similarities and propensity to thrombotic complications and leukaemic transformation. Current therapeutic options are limited in disease-modifying activity with a focus on the prevention of thrombus formation. Constitutive activation of the JAK/STAT signalling pathway is a hallmark of pathogenesis across the disease spectrum with driving mutations in JAK2, CALR and MPL identified in the majority of patients. Co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control and splicing of RNA are variably but recurrently identified across the MPN disease spectrum, whilst epigenetic contributors to disease are increasingly recognised. The prognostic implications of one MPN diagnosis may significantly limit life expectancy, whilst another may have limited impact depending on the disease phenotype, genotype and other external factors. The genetic and clinical similarities and differences in these disorders have provided a unique opportunity to understand the relative contributions to MPN, myeloid and cancer biology generally from specific genetic and epigenetic changes. This review provides a comprehensive overview of the molecular pathophysiology of MPN exploring the role of driver mutations, co-occurring mutations, dysregulation of intrinsic cell signalling, epigenetic regulation and genetic predisposing factors highlighting important areas for future consideration.

Keywords: Essential thrombocythaemia; Myeloproliferative neoplasms; Polycythaemia vera; Primary myelofibrosis.

Fig. 1

MPN Heterogeneity. A figure demonstrating the distinct clinical entities observed in MPN patients with a summary of distinguishing clinical features observed in each. *Propensity to enhanced rates of clot formation in ET appear to be variable depending on driver mutation status. **Bleeding can manifest in a minority of ET patients resulting from acquired Von Willebrand disease resulting from very high platelet counts

Fig. 2

Activated signalling in MPN. Activated signalling pathways in MPN include JAK/STAT signalling, PI3K/AKT and MAPK (RAS/MEK/ERK) cascades. The balance of predominant STAT1/3/5 signalling may impact on ultimate disease phenotype, whilst persistence of activated MAPK or PI3K signalling or STAT serine phosphorylation may occur despite JAK inhibitor therapy. Examples of intracellular negative regulators of JAK/STAT, PI3K/AKT and MAPK signalling with potential roles in MPN pathophysiology are also shown

Fig. 3

Mutational significance in MPN for overall survival. A summary of determined mutational significance in MPN. The central figure shows genetic contributors to fibrotic (inner yellow ring) and leukaemic (outer red ring) transformation in MPN determined by a predictive modelling approach in 1599 chronic phase and 276 myelofibrosis patients [15]. Underlined genes were contributors to death in myelofibrosis patients in this modelling. Overlaid are a purple ring (A) showing independent risk factors for survival identified in 641 myelofibrosis patients [101], a green ring (B) showing independent risk factors for survival identified in 483 myelofibrosis patients and validated in a further 396 patients [98], and finally a grey ring (C) showing prognostically detrimental genes in 537 myelofibrosis patients and validated in a further 260 patients [102]

Fig. 4

Effects of mutation order in MPN. Order of mutation acquisition affects both self-renewal capacity of mutants in the haematopoietic stem cell compartment and proliferative drive ultimately affecting the probability of producing a PV or ET phenotype