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.

Keywords: JAK2V617F; MPN.

Figure 1

The structure of JAK2. (A) The domain organization of full length JAK2. (B) JAK2 domains and linkers were adapted from PDB and drawn in different colors. FERM (band 4.1, ezrin, radixin, moesin) domain colored in brown, SH2 (an Src homology 2) domain colored in green, JH2 (Jak-homology 2) domain colored in yellow, JH1 (Janus homology-1) domain colored in light blue, FERM-SH2 linker colored in red, SH2-JH2 linker colored in blue, and JH2-JH1 colored in magenta. FERM, FERM-SH2 linker, SH2, and SH2-JH2 linker (PDBID: 6E2Q); JH1 (PDBID: 6VNE); JH2 (PDBID: 5I4N); and JH1-JH2 linker (PDBID: 4OLI).

Figure 2

Typical and JAK2V617F induced dysregulated JAK2-STAT signaling. Normal JAK-STAT signaling is mediated by cytokines and growth factors, for instance, EPO and TPO, which maintain an ordered balance of cell proliferation and differentiation by self-renewal in HSC cell pool and are essential for normal blood cell formation (left panel). The JAK2V617F mutation causes JAK2 to be more sensitive to cytokines and consistently activates the JAK-STAT pathway. The over-activation of JAK2-STAT signaling alters the critical cell fate and leads to more progenitor cell development and further progression to MPN (right panel).

Figure 3

Model of the interactions between the domains of the JAK2 protein. The three main states of JAK2 include auto-inhibited state, unphosphorylated state, and active state. In the auto-inhibited state, the protein with phosphorylated S523 (pS523) and phosphorylated Y570 (pY570) are locked in the inactive conformation. The unphosphorylated state is a transition between the active and inactive conformations. In the active state, the two JAK2 molecules associated with a cytokine receptor dimer are maintained in positions that trans-phosphorylation of the JH1 activation loop, including Tyr1007 and Tyr1008. The pS523 is drawn as a blue dot, the pY570 is drawn as a red dot, the V617F mutation is drawn as a red star, and the pY1007/1008 is drawn as green dots.

Figure 4

Model of JAK2V617F positive contributing to MPN phenotype.