JAK2 46/1 (GGCC) Haplotype: A Biomarker for Oncogenesis, Risk Stratification, and Drug Resistance in Myeloproliferative Neoplasms

Background: The JAK2 46/1 ("GGCC") haplotype, is an inherited genetic variation within the JAK2 gene locus that has become a focal point in research related to oncogenesis, particularly in myeloproliferative neoplasms (MPNs). Methods: We conducted a narrative review of landmark discoveries in hematological malignancies and JAK2, focusing its role on oncogenesis, risk stratification, and drug resistance in MPNs. Results: This haplotype spans several polymorphisms within the JAK2 gene. It has been found to increase susceptibility to a variety of hematologic cancers, especially when linked with the somatic JAK2 V617F mutation, which results in the alteration of the JAK/STAT pathway, which is particularly essential for hematopoiesis. The “GGCC” part is characterized by four SNPs, with the G allele of the rs10974944 SNP in this haplotype correlated with MPNs progressing to myelofibrosis. Moreover, the G allele seems to be crucial for the predisposition to onco-drug resistance onset. Conclusion: Identifying the 46/1 haplotype in patients may not only enhance risk stratification for JAK2-driven cancers but also guide more effective, personalized therapeutic strategies to overcome resistance. Thus, this review aims to describe current knowledge about the JAK2 46/1 haplotype as a marker for diagnosis and the prediction of disease outcome.