Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms

Abstract

Myeloproliferative neoplasms (MPN) are a group of blood cancers in which the bone marrow (BM) produces an overabundance of erythrocyte, white blood cells, or platelets. Philadelphia chromosome-negative MPN has three subtypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The over proliferation of blood cells is often associated with somatic mutations, such as JAK2, CALR, and MPL. JAK2V617F is present in 95% of PV and 50–60% of ET and PMF. Based on current molecular dynamics simulations of full JAK2 and the crystal structure of individual domains, it suggests that JAK2 maintains basal activity through self-inhibition, whereas other domains and linkers directly/indirectly enhance this self-inhibited state. Nevertheless, the JAK2V617F mutation is not the only determinant of MPN phenotype, as many normal individuals carry the JAK2V617F mutation without a disease phenotype. Here we review the major MPN phenotypes, JAK-STAT pathways, and mechanisms of development based on structural biology, while also describing the impact of other contributing factors such as gene mutation allele burden, JAK-STAT-related signaling pathways, epigenetic modifications, immune responses, and lifestyle on different MPN phenotypes. The cross-linking of these elements constitutes a complex network of interactions and generates differences in individual and cellular contexts that determine the phenotypic development of MPN.

The Contribution of JAK2 46/1 Haplotype in the Predisposition to Myeloproliferative Neoplasms

“…The latter is possibly related to individual characteristics (sex, associated inflammatory disease), and genetic abnormalities (driver genes, pathogenic genetic variants and other chromosomal aberrations) [ 71 ]. Different signaling pathways, epigenetic modulation, immune system, lifestyle, JAK2V617F variant allele load, and exceptional germline alleles found in population-wide and hereditary cases are other possible factors involved in the development of JAK2V617F73-associated MPNs [ 71 , 72 ]. The discovery of this genetic alteration has brought benefits for the therapy and diagnosis of MPNs; however, some questions remain unclear, such as the events that precede its acquisition, since it is not a germline genetic variant [ 29 ].…”

The clinical relevance of broad mutational screening of myeloproliferative neoplasms at diagnosis

“…If the JAK2 mutation precedes mutation in DNMT3A or TET2 , the phenotypic picture would likely be PV. If mutations instead occur in reverse order, the MPN phenotype would likely be ET ( 22 ). Host factors also contribute to the development of disease ( 22 , 23 ).…”

Exploring hematological alterations and genetics linked to SNV rs10974944 in myeloproliferative neoplasms among Amazon patients

“…JAK2 V617F (dbSNP ID: rs77375493 ) is the main genetic finding in MPNs and has a frequency of 95% in PV cases and between 50–60% in ET and MF cases 4 . This somatic variant triggers the substitution of valine by phenylalanine at codon 617, which alters the pseudo-kinase domain of the JAK2 protein and conditions a constitutive activation of the JAK/STAT signaling pathway 5 .…”