Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo

Detalhes bibliográficos
Autor(a) principal: Torres, Dania Isamary Gutierrez
Data de Publicação: 2022
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Repositório Institucional da Universidade do Estado do Amazonas (UEA)
Texto Completo: https://ri.uea.edu.br/handle/riuea/2228
Resumo: BCR/ABL1 negative chronic myeloproliferative neoplasms are clonal diseases caused by aberrant proliferation of hematopoietic cells in the bone marrow and excessive accumulation of mature blood elements in peripheral blood. Polycythemia vera, essential thrombocythemia and primary myelofibrosis are the most classic entities within this classification of hematological diseases, which have in common genetic rearrangements in one of the main intracellular signaling pathways: the JAK2/STAT5 pathway. The JAK2 gene encodes the Janus kinase 2 (JAK2) protein, involved in cell proliferation and differentiation processes. JAK2V617F is the most frequent and most studied variant in this group of diseases due to its ability to generate several clinical phenotypes. Variants on exon 12 of the JAK2 gene are screened in JAK2V617F negative individuals, comprising approximately 3% of cases. Although JAK2V617F and JAK2 exon 12 variants are the main research targets in BCR/ABL1 negative Chronic Myeloproliferative Neoplasms, new variants throughout the gene have been identified. Objective: The study aimed to molecularly characterize variants in the JAK2 gene in patients with BCR/ABL1 negative Chronic Myeloproliferative Neoplasms: Polycythemia vera, Essential Thrombocythemia and Myelofibrosis. Methodology: We evaluated 75 patients diagnosed with BCR/ABL1 negative myeloproliferative neoplasms: Polycythemia vera, Essential Thrombocythemia and Myelofibrosis. Clinical data were obtained from medical records. Laboratory data were obtained from sample collections during the follow-up of subjects. Molecular evaluation was performed using conventional Polymerase Chain Reaction and Sanger Sequencing to detect variants in the coding region of the JAK2 gene. Statistical analysis of categorical variables was performed using the Chi-Square test. Kruskal-Wallis and Mann-Whitney tests were used to analyze numerical variables, when convenient. p <0.05 values were considered statistically significant. Results: Sanger sequencing demonstrated the presence of rs907414891, rs2230722, rs2230723, rs10119726, rs576746768, rs77375493 (JAK2V617F), rs2230728, rs2230724, rs41316003 and rs55930140 in the coding region of the JAK2 gene, considering rs77375493 the most frequent variant in individuals with Polycythemia vera. Coexistence of variants was detected in Polycythemia vera and Thrombocythemia, with the combination of variants rs2230722/rs77375493/rs2230724 being the most predominant in both hematological diseases with evidence of alterations in hematological parameters. Conclusions: Individuals with BCR/ABL1 negative chronic myeloproliferative neoplasms with the rs2230724, rs2230722 and rs77375493 variants both separately and together show slight alterations in the clinical-laboratory profile, especially in concomitance with the rs77375493 variant, demonstrating involvement in the instability of regulatory mechanisms at the protein level and possibly the myeloproliferative phenotype
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spelling Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativoMolecular characterization of JAK2 gene variants in patients with BCR/ABL1 negative chronic myeloproliferative neoplasmsJanus quinaseNeoplasias Mieloproliferativas crônicasinalização intracelulaSequenciamento de SangerChronic myeloproliferative neoplasmsBCR/ABL1 negative chronic myeloproliferative neoplasms are clonal diseases caused by aberrant proliferation of hematopoietic cells in the bone marrow and excessive accumulation of mature blood elements in peripheral blood. Polycythemia vera, essential thrombocythemia and primary myelofibrosis are the most classic entities within this classification of hematological diseases, which have in common genetic rearrangements in one of the main intracellular signaling pathways: the JAK2/STAT5 pathway. The JAK2 gene encodes the Janus kinase 2 (JAK2) protein, involved in cell proliferation and differentiation processes. JAK2V617F is the most frequent and most studied variant in this group of diseases due to its ability to generate several clinical phenotypes. Variants on exon 12 of the JAK2 gene are screened in JAK2V617F negative individuals, comprising approximately 3% of cases. Although JAK2V617F and JAK2 exon 12 variants are the main research targets in BCR/ABL1 negative Chronic Myeloproliferative Neoplasms, new variants throughout the gene have been identified. Objective: The study aimed to molecularly characterize variants in the JAK2 gene in patients with BCR/ABL1 negative Chronic Myeloproliferative Neoplasms: Polycythemia vera, Essential Thrombocythemia and Myelofibrosis. Methodology: We evaluated 75 patients diagnosed with BCR/ABL1 negative myeloproliferative neoplasms: Polycythemia vera, Essential Thrombocythemia and Myelofibrosis. Clinical data were obtained from medical records. Laboratory data were obtained from sample collections during the follow-up of subjects. Molecular evaluation was performed using conventional Polymerase Chain Reaction and Sanger Sequencing to detect variants in the coding region of the JAK2 gene. Statistical analysis of categorical variables was performed using the Chi-Square test. Kruskal-Wallis and Mann-Whitney tests were used to analyze numerical variables, when convenient. p <0.05 values were considered statistically significant. Results: Sanger sequencing demonstrated the presence of rs907414891, rs2230722, rs2230723, rs10119726, rs576746768, rs77375493 (JAK2V617F), rs2230728, rs2230724, rs41316003 and rs55930140 in the coding region of the JAK2 gene, considering rs77375493 the most frequent variant in individuals with Polycythemia vera. Coexistence of variants was detected in Polycythemia vera and Thrombocythemia, with the combination of variants rs2230722/rs77375493/rs2230724 being the most predominant in both hematological diseases with evidence of alterations in hematological parameters. Conclusions: Individuals with BCR/ABL1 negative chronic myeloproliferative neoplasms with the rs2230724, rs2230722 and rs77375493 variants both separately and together show slight alterations in the clinical-laboratory profile, especially in concomitance with the rs77375493 variant, demonstrating involvement in the instability of regulatory mechanisms at the protein level and possibly the myeloproliferative phenotypeAs neoplasias mieloproliferativas crônicas BCR/ABL1 negativo são doenças clonais causadas pela proliferação aberrante de células hematopoiéticas na medula óssea e acumulação excessiva de elementos sanguíneos maduros no sangue periférico. Policitemia vera, trombocitemia essencial e mielofibrose primária constituem as entidades mais clássicas dentro desta classificação de doenças hematológicas, as quais têm em comum rearranjos genéticos em uma das principais vias de sinalização intracelular: a via JAK2/STAT5. O gene JAK2 codifica a proteína Janus quinase 2 (JAK2), envolvida em processos de proliferação e diferenciação celular. JAK2V617F é a variante mais frequente e de maior estudo neste grupo de doenças pela habilidade de gerar diversos fenótipos clínicos. Variantes no éxon 12 do gene JAK2 pesquisam-se em indivíduos JAK2V617F negativos, compreendendo aproximadamente 3% dos casos. Embora JAK2V617F e variantes no éxon 12 de JAK2 constituam os principais alvos de pesquisa nas Neoplasias Mieloproliferativas crônicas BCR/ABL1 negativo, novas variantes em toda a extensão do gene têm sido identificadas. Objetivo: O estudo visou caracterizar molecularmente variantes no gene JAK2 em pacientes com Neoplasias Mieloproliferativas Crônicas BCR/ABL1 negativo: Policitemia vera, Trombocitemia Essencial e Mielofibrose. Metodologia: Foram avaliados 75 pacientes com diagnóstico de neoplasias mieloproliferativas BCR/ABL1 negativo: Policitemia vera, Trombocitemia essencial e Mielofibrose. Dados clínicos obtiveram-se de prontuários médicos. Dados laboratoriais obtiveram-se de coletas de amostras durante o seguimento dos indivíduos. Realizou-se avaliação molecular mediante Reação em cadeia de Polimerase convencional e Sequenciamento de Sanger para detecção de variantes na região codificante do gene JAK2. Análise estatística de variáveis categóricas foi realizada pelo teste Qui-Quadrado. Os testes Kruskal-Wallis e Mann-Whitney foram utilizados para análise de variáveis numéricas, quando for conveniente. Valores de p < 0.05 consideraram-se estatisticamente significativos Resultados: Sequenciamento de Sanger demonstrou a presença de rs907414891, rs2230722, rs2230723, rs10119726, rs576746768, rs77375493 (JAK2V617F), rs2230728, rs2230724, rs41316003 e rs55930140 na região codificante do gene JAK2, considerando rs77375493 a variante mais frequente em indivíduos com Policitemia vera. Coexistência de variantes detectou-se na policitemia vera e na trombocitemia, sendo a combinação de variantes rs2230722/ rs77375493 /rs2230724 a mais predominante em ambas doenças hematológicas com evidência de alterações em parâmetros hematológicos. Conclusões: indivíduos com Neoplasias Mieloproliferativas crônicas BCR/ABL1 negativo com as variantes rs2230724, rs2230722 e rs77375493 tanto separada como conjuntamente evidenciam alterações discretas no perfil clínico-laboratorial, especialmente em concomitância com a variante rs77375493, demonstrando envolvimento na instabilidade de mecanismos regulatórios em nível proteico e possivelmente no fenótipo mieloproliferativoUniversidade do Estado do AmazonasBrasilUEAPROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS APLICADAS À HEMATOLOGIATarragô, Andréa MonteiroMourão, Lucivana de SouzaPassos, Leny Nascimento da MottaSadahiro, AyaTorres, Katia LuzTorres, Dania Isamary Gutierrez2022-08-10T16:07:44Z2024-09-05T18:56:15Z2022-07-292022-08-10T16:07:44Z2022-05-20info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesisapplication/pdfhttps://ri.uea.edu.br/handle/riuea/2228por56 7. Bortolheiro, T.C.; Chiattone, C.S. Leucemia mielóide crônica: História natural e classificação. Rev. Bras. 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dc.title.none.fl_str_mv Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
Molecular characterization of JAK2 gene variants in patients with BCR/ABL1 negative chronic myeloproliferative neoplasms
title Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
spellingShingle Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
Torres, Dania Isamary Gutierrez
Janus quinase
Neoplasias Mieloproliferativas crônicas
inalização intracelula
Sequenciamento de Sanger
Chronic myeloproliferative neoplasms
title_short Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
title_full Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
title_fullStr Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
title_full_unstemmed Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
title_sort Caracterização molecular de variantes no gene JAK2 em pacientes com neoplasias mieloproliferativas crônicas BCR/ABL1 negativo
author Torres, Dania Isamary Gutierrez
author_facet Torres, Dania Isamary Gutierrez
author_role author
dc.contributor.none.fl_str_mv Tarragô, Andréa Monteiro
Mourão, Lucivana de Souza
Passos, Leny Nascimento da Motta
Sadahiro, Aya
Torres, Katia Luz
dc.contributor.author.fl_str_mv Torres, Dania Isamary Gutierrez
dc.subject.por.fl_str_mv Janus quinase
Neoplasias Mieloproliferativas crônicas
inalização intracelula
Sequenciamento de Sanger
Chronic myeloproliferative neoplasms
topic Janus quinase
Neoplasias Mieloproliferativas crônicas
inalização intracelula
Sequenciamento de Sanger
Chronic myeloproliferative neoplasms
description BCR/ABL1 negative chronic myeloproliferative neoplasms are clonal diseases caused by aberrant proliferation of hematopoietic cells in the bone marrow and excessive accumulation of mature blood elements in peripheral blood. Polycythemia vera, essential thrombocythemia and primary myelofibrosis are the most classic entities within this classification of hematological diseases, which have in common genetic rearrangements in one of the main intracellular signaling pathways: the JAK2/STAT5 pathway. The JAK2 gene encodes the Janus kinase 2 (JAK2) protein, involved in cell proliferation and differentiation processes. JAK2V617F is the most frequent and most studied variant in this group of diseases due to its ability to generate several clinical phenotypes. Variants on exon 12 of the JAK2 gene are screened in JAK2V617F negative individuals, comprising approximately 3% of cases. Although JAK2V617F and JAK2 exon 12 variants are the main research targets in BCR/ABL1 negative Chronic Myeloproliferative Neoplasms, new variants throughout the gene have been identified. Objective: The study aimed to molecularly characterize variants in the JAK2 gene in patients with BCR/ABL1 negative Chronic Myeloproliferative Neoplasms: Polycythemia vera, Essential Thrombocythemia and Myelofibrosis. Methodology: We evaluated 75 patients diagnosed with BCR/ABL1 negative myeloproliferative neoplasms: Polycythemia vera, Essential Thrombocythemia and Myelofibrosis. Clinical data were obtained from medical records. Laboratory data were obtained from sample collections during the follow-up of subjects. Molecular evaluation was performed using conventional Polymerase Chain Reaction and Sanger Sequencing to detect variants in the coding region of the JAK2 gene. Statistical analysis of categorical variables was performed using the Chi-Square test. Kruskal-Wallis and Mann-Whitney tests were used to analyze numerical variables, when convenient. p <0.05 values were considered statistically significant. Results: Sanger sequencing demonstrated the presence of rs907414891, rs2230722, rs2230723, rs10119726, rs576746768, rs77375493 (JAK2V617F), rs2230728, rs2230724, rs41316003 and rs55930140 in the coding region of the JAK2 gene, considering rs77375493 the most frequent variant in individuals with Polycythemia vera. Coexistence of variants was detected in Polycythemia vera and Thrombocythemia, with the combination of variants rs2230722/rs77375493/rs2230724 being the most predominant in both hematological diseases with evidence of alterations in hematological parameters. Conclusions: Individuals with BCR/ABL1 negative chronic myeloproliferative neoplasms with the rs2230724, rs2230722 and rs77375493 variants both separately and together show slight alterations in the clinical-laboratory profile, especially in concomitance with the rs77375493 variant, demonstrating involvement in the instability of regulatory mechanisms at the protein level and possibly the myeloproliferative phenotype
publishDate 2022
dc.date.none.fl_str_mv 2022-08-10T16:07:44Z
2022-07-29
2022-08-10T16:07:44Z
2022-05-20
2024-09-05T18:56:15Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://ri.uea.edu.br/handle/riuea/2228
url https://ri.uea.edu.br/handle/riuea/2228
dc.language.iso.fl_str_mv por
language por
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dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
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dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Universidade do Estado do Amazonas
Brasil
UEA
PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS APLICADAS À HEMATOLOGIA
publisher.none.fl_str_mv Universidade do Estado do Amazonas
Brasil
UEA
PROGRAMA DE PÓS-GRADUAÇÃO EM CIÊNCIAS APLICADAS À HEMATOLOGIA
dc.source.none.fl_str_mv reponame:Repositório Institucional da Universidade do Estado do Amazonas (UEA)
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instacron:UEA
instname_str Universidade do Estado do Amazonas (UEA)
instacron_str UEA
institution UEA
reponame_str Repositório Institucional da Universidade do Estado do Amazonas (UEA)
collection Repositório Institucional da Universidade do Estado do Amazonas (UEA)
repository.name.fl_str_mv Repositório Institucional da Universidade do Estado do Amazonas (UEA) - Universidade do Estado do Amazonas (UEA)
repository.mail.fl_str_mv bibliotecacentral@uea.edu.br
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