Genetic Background of Polycythemia Vera

Abstract

Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations triggering PV-phenotype with the V617F mutation detected in nearly 98% of cases. That's why JAK2 targeting therapeutic strategies have rapidly emerged to counter the aggravation of the disease. Over decades of research, to go further in the understanding of the disease and its evolution, a wide panel of genetic alterations affecting multiple genes has been highlighted. These are mainly involved in alternative splicing, epigenetic, miRNA regulation, intracellular signaling, and transcription factors expression. If JAK2 mutation, irrespective of the nature of the alteration, is known to be a crucial event for the disease to initiate, additional mutations seem to be markers of progression and poor prognosis. These discoveries have helped to characterize the complex genomic landscape of PV, resulting in potentially new adapted therapeutic strategies for patients concerning all the genetic interferences.

Keywords: JAK2 mutation; erythrocytosis; mutational landscape; myeloproliferative neoplasm; polycythemia vera.

Figure 1

Schematic view of JAK2 gene structure and its mutational landscape in PV. JAK2 gene is found on chromosome 9 at 9p24.1 (4,984,390–5,129,948) location. It is composed of 7 homology domains (JH1 to JH7) that correlate to 4 functional domains: FERM, SH2, Pseudokinase, and Kinase domains. In PV, the mutations affected the region of JAK2 span from exon 12 to exon 15 and mainly belong to the JH2/Pseudokinase-domain. Abbreviation: del = deletion; FERM = four-point-one, ezrin, radixin, moesin; JH = Jak homology region; SH2 = src homology 2 domain.

Figure 2

Graphical sum-up of 7 PV patients cohort/case reports (total = 205 patients). Each column represents one patient with all his mutational landscape divided by affected pathway (Driver mutations, Epigenetic, Alternative splicing, Intracellular signaling and Transcription factors). Cohort/case report references: Cohort 1 [5], Cohort 2 [176], Case report 1 [173], Case report 2 [175], Cohort 3 [92], Case report 3 [151] and Cohort 4 [17]. Abbreviations: C.1 = Case report 1; C.2 = Case report 2; C.3 = Case report 3.

Figure 3

Overview of JAK2/MNAMs association in PV (total = 268 combinations) (based on Figure 2 related data). A visual dot plot representation of JAK2 associated mutations grouped by pathway (A) and individual affected gene (B) (each circle represents 1% of the total). Abbreviation: Alt. Splicing = Alternative Splicing; Intra. signaling = Intracellular signaling; Trans. factor = Transcription factor.

Figure 4

Heat map view of JAK2 paring with additional MNAMs in 7 PV patients cohort reports (Figure 2). (A) Heat map representation of JAK2/affected pathway association with another MNAM that belongs to one of the 5 affected pathways (e.g., the triple association of JAK2 + one of epigenetic affected gene + one of intracellular signaling affected gene is found in 20 cases among the total of 175 cases affected by a JAK2/Epigenetic association). The numbers above each colon represent the total cases of each JAK2/affected pathway (e.g., association of JAK2 + one of epigenetic affected gene is found in 175 cases). (B) Heat map representation of JAK2/affected gene with another MNAM (e.g., the triple association of JAK2 + TET2 + ASXL1 is found in 9 cases among the 101 cases affected by a JAK2/TET2 association.). The numbers above each colon represent the total cases of each JAK2/MNAM association (e.g., association of JAK2 + TET2 is found in 101 cases). Abbreviation: Alt. splicing = Alternative splicing; Epi. = Epigenetic; Intra. sign. = Intracellular signaling; Trans. factor = Transcription factor.