Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis

Autor(es):Mostrar menos -

Tognon, Raquel ^[1] ; Gasparotto, Elainy P. L. ^[1] ; Neves, Renata P. ^[1] ; Nunes, Natalia S. ^[1] ; Ferreira, Aline F. ^[1] ; Palma, Patricia V. B. ^[2] ; Kashima, Simone ^[2] ; Covas, Dimas T. ^{[2, 3]} ; Santana, Mary ^[4] ; Souto, Elizabeth X. ^[4] ; Zanichelli, Maria Aparecida ^[5] ; Simoes, Belinda P. ^[3] ; de Souza, Ana Maria ^[1] ; Castro, Fabiola A. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Clin Toxicol & Bromatol Anal, Ribeirao Preto Sch Pharmaceut Sci, BR-14049 Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Reg Blood Ctr Ribeirao Preto, Ribeirao Preto Sch Med, Clin Hosp, BR-14049 Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Dept Clin Med, Ribeirao Preto Sch Med, BR-14049 Ribeirao Preto - Brazil

^[4] Brigadeiro Hosp Sao Paulo, Sao Paulo - Brazil

^[5] Inst Canc Treatment Children ITACI, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Hematology & Oncology; v. 5, FEB 2 2012.
• Citações Web of Science: 14

Resumo

Background: Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Chronic Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation/myeloaccumulation without cell maturation impairment. The JAK2 V617F mutation and PRV1 gene overexpression may contribute to MPN physiopathology. We hypothesized that deregulation of the apoptotic machinery may also play a role in the pathogenesis of ET and PMF. In this study we evaluated the apoptosis-related gene and protein expression of BCL2 family members in bone marrow CD34(+) hematopoietic stem cells (HSC) and peripheral blood leukocytes from ET and PMF patients. We also tested whether the gene expression results were correlated with JAK2 V617F allele burden percentage, PRV1 overexpression, and clinical and laboratory parameters. Results: By real time PCR assay, we observed that A1, MCL1, BIK and BID, as well as A1, BCLW and BAK gene expression were increased in ET and PMF CD34(+) cells respectively, while pro-apoptotic BAX and anti-apoptotic BCL2 mRNA levels were found to be lower in ET and PMF CD34(+) cells respectively, in relation to controls. In patients' leukocytes, we detected an upregulation of anti-apoptotic genes A1, BCL2, BCL-XL and BCLW. In contrast, pro-apoptotic BID and BIMEL expression were downregulated in ET leukocytes. Increased BCL-XL protein expression in PMF leukocytes and decreased BID protein expression in ET leukocytes were observed by Western Blot. In ET leukocytes, we found a correlation between JAK2 V617F allele burden and BAX, BIK and BAD gene expression and between A1, BAX and BIK and PRV1 gene expression. A negative correlation between PRV1 gene expression and platelet count was observed, as well as a positive correlation between PRV1 gene expression and splenomegaly. Conclusions: Our results suggest the participation of intrinsic apoptosis pathway in the MPN physiopathology. In addition, PRV1 and JAK2 V617F allele burden were linked to deregulation of the apoptotic machinery. (AU)

• Processo FAPESP: 08/54387-5 - Expressão de proteínas e genes pró e anti-apoptóticos na mielofibrose e trombocitemia essencial
• Beneficiário: Raquel Tognon Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 10/01756-3 - Expressão de MicroRNAs em células CD34+ e leucócitos em Policitemia Vera.
• Beneficiário: Natália de Souza Nunes
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 06/50094-8 - Expressão de gênese de proteínas pró e antiapoptóticas em doenças mieloproliferativas crônicas
• Beneficiário: Fabíola Attié de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 08/52049-5 - Expressão de microRNAs em células Bcr-Abl positivas: associação com resistência à apoptose e fisiopatologia da leucemia mielóide crônica
• Beneficiário: Aline Fernanda Ferreira
• Modalidade de apoio: Bolsas no Brasil - Doutorado