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

Abstract

Haplotype 46/1 (GGCC) consists of a set of genetic variations distributed along chromosome 9p.24.1, which extend from the Janus Kinase 2 gene to Insulin like 4. Marked by four jointly inherited variants (rs3780367, rs10974944, rs12343867, and rs1159782), this haplotype has a strong association with the development of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) because it precedes the acquisition of the JAK2V617F variant, a common genetic alteration in individuals with these hematological malignancies. It is also described as one of the factors that increases the risk of familial MPNs by more than five times, 46/1 is associated with events related to inflammatory dysregulation, splenomegaly, splanchnic vein thrombosis, Budd-Chiari syndrome, increases in RBC count, platelets, leukocytes, hematocrit, and hemoglobin, which are characteristic of MPNs, as well as other findings that are still being elucidated and which are of great interest for the etiopathological understanding of these hematological neoplasms. Considering these factors, the present review aims to describe the main findings and discussions involving the 46/1 haplotype, and highlights the molecular and immunological aspects and their relevance as a tool for clinical practice and investigation of familial cases.

Keywords: JAK2 germline haplotype; haplotype; molecular pathogenesis; myeloid neoplasms; single nucleotide polymorphisms.

Figure 1

Mechanisms related to acquired uniparental disomy in hematopoietic pluripotent stem cells. This process can occur due to (1) (A) nondisjunction of sister chromatids or (B) delay in anaphase causing trisomy and monosomy of one of the chromosomes of the set, where in the cell with monosomy there is duplication of the remaining chromosome in the attempt to balance the loss of a chromosome, which results in two identical chromosomes in the same cell; or by (2) reciprocal exchange of chromosomal material during mitosis (mitotic recombination), such as chromatids, which generates several possible outcomes. In this example, applied to chromosome 9, the presence of the 46/1 haplotype and the JAK2V617F variant is illustrated, and is conditioned to the state of homozygosity.

Figure 2

Schematic representation of the 46/1 haplotype based on the JAK2 gene reference sequence (NG_009904). The haplotype extends over a block with approximately 250–280 kb on chromosome 9p, and encompasses three genes (JAK2, INSL6, and INSL4) and regions with a high rate of genetic variants in JAK2, such as exon 12 (with alterations such as insertions, deletions, and substitutions) and exon 14 (location of JAK2V617F). Four variants (rs3780367, rs10974944, rs12343867, and rs1159782) mark the haplotype and establish another nomenclature based on the variant alleles, GGCC, as also mentioned in the literature [97].

Figure 3

Location of variants identified in studies targeting the 46/1 haplotype. The mapping of variants along the gene was performed based on the reference sequence (NG_009904).

Figure 4

Minor allele frequency (MAF) of the 46/1 haplotype markers. Frequencies were measured from samples collected from individuals from Puerto Rico, Colombia, Peru, Gambia, Nigeria, Kenya, Italy, France, United Kingdom, Finland, Pakistan, India, China, Japan, and of Mexican origin residing in California and Texas (United States) [104,105,106,107,108].

Figure 5

Possible association of the 46/1 haplotype and MPNs. (1) Medullary stromal cells positive for 46/1 may show dysregulation in genes, such as INSL4 and INSL6, which may be involved in the (2) excessive production of proinflammatory and promyeloid mediators. These cytokines (3) interact with normal and haplotype-positive and JAK2V617F multipotent stem cells, promoting (4) exacerbated proliferation (proliferative advantage) of the mutated cells, which, in turn, continue their process of (5) differentiation and cell maturation, and trigger the (6) clonal myeloproliferative disorder.