Myeloproliferative neoplasms: from origins to outcomes

Abstract

Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.

The identification of fibrosis-driving myofibroblast precursors reveals new therapeutic avenues in myelofibrosis

“…Thus, there is a need to identify additional pathways that might be involved in the development and maintenance of MPN-mutant clones, which could be targeted in combination with JAK inhibition for improved therapeutic benefit. [35][36][37] Identifying novel and effective antifibrotic therapeutics that have minor adverse effects in both solid organ fibrosis and MF is the holy grail in fibrosis research. Various antifibrotic strategies in solid organs and MF aim to target inflammation and fibrogenic cytokines, such as PDGF and transforming growth factor b (TGF-b), among various others.…”

“…A simplified description of this process states that in PMF (or in MPNs in general), hematopoietic stem cells (HSCs) acquire mutations, in most of the cases a JAK2 V617F mutation, which leads to increased proliferation of the HSC and replacement of normal blood formation. [3][4][5][6][7][8] In the course of the disease, nonmutated, nonhematopoietic cells transform into fibrosis-driving cells. The biology of this cross talk between malignant hematopoietic cells and a normal (nonhematopoietic) stromal cell that transforms into a fibrosis-driving cell remained elusive for decades; the cells driving fibrosis were just identified in 2017.…”

Genetics, prognosis, and transplantation for myelofibrosis

“…Nangalia and Green, Zoi and Cross, and Spivak have recently reviewed our current understanding of the genomics, pathogenesis, and pathophysiology of MPN, emphasizing the central role of deregulation of JAK‐STAT signaling in MPNs. Available data indicate that single nucleotide variants, as present for example on the haplotype designated 46/1, are associated with an increased risk of activating JAK2 mutations, consistent with genetic predisposition to develop MPN.…”

“…Mutations in EZH2 (enhancer of zest homolog 2), the active component of the polycomb repressor complex 2, are associated with de‐repression of target genes that enhance self‐renewal of stem cells but also enhance fibrosis in the context of a JAK2 (V617F) mutation . Nangalia and Green emphasize the importance of the order in which mutations occur . Patients in whom the JAK2 mutation presents first (followed but TET2 or DNMT3A ) generally have double mutants, are younger and show the PV phenotype, whereas patients who acquire the TET2 mutation first typically have single mutant cells, are older and more likely present with ET .…”

Genetic Predisposition to Myeloproliferative Neoplasms: Another Piece of the Puzzle

“…Research into the mechanisms underlying predisposition to MPN have discovered candidate genetic variants, which segregate into 1 of the following categories: rare genetic variants, found in a small number of families with a high penetrance for disease, or common variants that are prevalent in the population and result in a small increased risk to develop MPN. Two models through which germline variation may increase MPN incidence were suggested [3]: DNA hypermutability, in which certain genetic variants/ haplotypes are genetically unstable and predispose to an increased somatic mutation rate, and permissive genetic background, where acquired mutations could have survival advantage in a certain milieu.…”