The JAK2V617F variant constitutes a genetic alteration of higher frequency in BCR/ABL1 negative chronic myeloproliferative neoplasms, which is caused by a substitution of a G ˃ T at position 1849 and results in the substitution of valine with phenylalanine at codon 617 of the polypeptide chain. Clinical, morphological and molecular genetic features define the diagnosis criteria of polycythemia vera, essential thrombocythemia and primary myelofibrosis. Currently, JAK2V617F is associated with clonal hematopoiesis, genomic instability, dysregulations in hemostasis and immune response. JAK2V617F clones induce an inflammatory immune response and lead to a process of immunothrombosis. Recent research has shown great interest in trying to understand the mechanisms associated with JAK2V617F signaling and activation of cellular and molecular responses that progressively contribute to the development of inflammatory and vascular conditions in association with chronic myeloproliferative neoplasms. Thus, the aim of this review is to describe the main genetic, hematological and immunological findings that are linked to JAK2 variant signaling in chronic myeloproliferative neoplasms.

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.

RESUMO Introdução: No processo de ensino, as estratégias de ensino, como as metodologias ativas, desempenham um papel fundamental na promoção da construção do conhecimento dos alunos, especialmente em disciplinas com temáticas e conteúdos científicos de difícil assimilação. Objetivo: Este estudo teve como objetivo avaliar a percepção dos alunos sobre as metodologias ativas usadas na disciplina de Genética Humana nos cursos de saúde de uma universidade pública do Amazonas. Método: Neste estudo, alunos de Enfermagem, Medicina e Odontologia responderam a um questionário com alternativas de respostas em escalas Likert sobre seis metodologias ativas na sala de aula: construção de modelo didático, gamificação, aprendizagem baseada em equipe, sala de aula invertida, estudo de casos clínicos e aprendizagem baseada em vídeo. Avaliou-se a confiabilidade das respostas, e testes qui-quadrado, Mann-Whitney e Kruskal-Wallis foram usados para análises de associação com nível de confiança de 95%. Resultado: Os participantes, em sua maioria mulheres, tinham uma média de idade de 20,4 ± 3,5 anos. Os alunos de Medicina foram os mais representativos em quatro das seis metodologias ativas usadas. Observou-se uma associação significativa entre o sexo feminino e a preferência pela metodologia de construção de modelo didático, enquanto o sexo masculino tendeu a avaliar mais positivamente a aprendizagem baseada em vídeo. Além disso, a análise individual revelou que a aprendizagem baseada em vídeo foi mais associada ao curso de Odontologia em comparação com Enfermagem, enquanto o estudo de casos clínicos foi mais favorecido pelos alunos de Medicina em comparação com Enfermagem. Isso sugere uma preferência dos estudantes de Odontologia e Medicina por essas metodologias, respectivamente. Quanto ao entendimento do conceito de metodologias ativas, a palavra “aluno” foi a mais frequentemente mencionada. Conclusão: Os alunos reconhecem o envolvimento direto das metodologias ativas, mas têm compreensão parcial dos benefícios. Metodologias ativas em genética humana motivaram e despertaram interesse. Docentes devem considerar a diversidade de competências e preferências dos alunos ao usarem tais metodologias, bem como compartilhar suas experiências e buscar uma educação permanente.

JAK2V617F (dbSNP: rs77375493) is the most frequent and most‑studied variant in BCR::ABL1 negative myeloproliferative neoplasms and in the JAK2 gene. The present study aimed to molecularly characterize variants in the complete coding region of the JAK2 gene in patients with BCR::ABL1 negative chronic myeloproliferative neoplasms. The study included 97 patients with BCR::ABL1 negative myeloproliferative neoplasms, including polycythemia vera (n=38), essential thrombocythemia (n=55), and myelofibrosis (n=04). Molecular evaluation was performed using conventional PCR and Sanger sequencing to detect variants in the complete coding region of the JAK2 gene. The presence of missense variants in the JAK2 gene including rs907414891, rs2230723, rs77375493 (JAK2V617F), and rs41316003 were identified. The coexistence of variants was detected in polycythemia vera and essential thrombocythemia. Thus, individuals with high JAK2V617F variant allele frequency (≥50% VAF) presented more thrombo‑hemorrhagic events and manifestations of splenomegaly compared with those with low JAK2V617F variant allele frequency (1 variant in the JAK2 gene, especially rs2230722, rs2230724, and rs77375493 variants, and those with high JAK2V617F VAF show alterations in the clinical‑laboratory profile compared with those with low JAK2V617F VAF.

BCR::ABL1-negative myeloproliferative neoplasms are hematopoietic disorders characterized by panmyelosis. JAK2 V617F is a frequent variant in these diseases and often occurs in the 46/1 haplotype. The G allele of rs10974944 has been shown to be associated with this variant, specifically its acquisition, correlations with familial cases, and laboratory alterations. This study evaluated the association between the 46/1 haplotype and JAK2 V617F in patients with myeloproliferative neoplasms in a population from the Brazilian Amazon. Clinical, laboratory and molecular sequencing analyses were considered. Carriers of the G allele of rs10974944 with polycythemia vera showed an increase in mean corpuscular volume and mean corpuscular hemoglobin, while in those with essential thrombocythemia, there was an elevation in red blood cells, hematocrit, and hemoglobin. Associations were observed between rs10974944 and the JAK2 V617F, in which the G allele (OR 3.4; p < 0.0001) and GG genotype (OR 4.9; p = 0.0016) were associated with JAK2 V617F + and an increase in variant allele frequency (GG: OR 15.8; p = < 0.0001; G: OR 6.0; p = 0.0002). These results suggest an association between rs10974944 (G) and a status for JAK2 V617F, JAK2 V617F + _VAF ≥ 50%, and laboratory alterations in the erythroid lineage.