Estudo do haplótipo 46/1 e promotor do gene JAK2 em pacientes com neoplasias mieloproliferativas BCR:: ABL 1 negativas atendidos na Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas

Abstract

BCR::ABL1 negative myeloproliferative neoplasms are hematological disorders characterized by hyperplasia of myeloid elements. Essential thrombocythemia, polycythemia vera, and myelofibrosis are the most frequent diseases within this group and can be differentiated by clinical, laboratory, and genetic findings. JAK2V617F is a common genetic alteration in BCR::ABL1- negative myeloproliferative neoplasms and is associated with the 46/1 haplotype, where the rs10974944 (C>G) variant is located in intron 12 of the JAK2 gene and serves as a genetic marker for this haplotype. This haplotype also influences laboratory alterations, allelic frequency of the variants, and correlations with familial myeloproliferative neoplasms. The promoter region also plays a role in the modulation within the etiopathogenic scenario of other neoplasms; however, little is still known about the action of variants in this gene segment in myeloproliferative diseases. Objective: To evaluate the presence of the 46/1 haplotype and the promoter region of the JAK2 gene. Methodology: The study included 108 individuals clinically diagnosed with polycythemia vera (n=39), essential thrombocythemia (n=61), and myelofibrosis (n=8). Clinical, laboratory, and molecular analyses using polymerase chain reaction and Sanger sequencing were important for obtaining the data. Results: In intron 12, in addition to rs10974944 (C>G), the variants rs10119004 (A>G), rs1081515 (G>T), and rs59720809 (A>G) were identified. Individuals with polycythemia vera and carriers of the rs10974944 G allele showed significantly increased mean corpuscular volume and mean corpuscular hemoglobin values (p < 0.05). On the other hand, the essential thrombocythemia group showed elevated levels of red blood cells, hematocrit, and hemoglobin (p < 0.05). An association was observed between the genotypic frequency of rs10974944 (G) and the status of the JAK2V617F variant. Individuals with the G allele and the GG genotype of rs10974944 showed a significant association with a positive status for JAK2V617F (p < 0.05), as well as an increased allelic frequency of the variant. Furthermore, rs10815151 showed an association with a negative status for JAK2V617F. In the promoter region, the variants rs6476933 (C>T), rs189703877 (A>C), rs73389454 (A>C), rs1887428 (G>C), and rs1887429 (G>T) were identified. The G allele of rs1887428 was more frequent in JAK2V617F-positive patients with a VAF≥50%, while the variant allele (C) showed an inverse relationship. rs6476933 (C>T), rs1887428 (G>C), and rs1887429 (G>T) apparently create transcription factor binding sites. Conclusion: rs10974944 (G) was found to be associated with a positive status for JAK2V617F, as well as laboratory alterations and an increase in the allelic frequency of the variant, while rs10815151 was shown to be a protective factor against JAK2V617F in the studied population. Additionally, rs1887428 likely plays a role in the regulation of JAK2, where the creation of a transcription factor binding site alters the gene expression.