The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells

Autor(es)

Carlos, Jorge Antonio Elias Godoy ; Lima, Keli ; Rego, Eduardo Magalha ; Costa-Lotufo, Leticia Veras ; Machado-Neto, Joao Agostinho

• Tipo de documento: Artigo Científico
• Fonte: Hematology, Transfusion and Cell Therapy; v. 46, p. 11-pg., 2024-12-19.

Resumo

The central role of the control of apoptosis in the pathophysiology of Philadelphia chromosome-negative myeloproliferative neoplasms has recently been reinforced in genetic and pharmacological studies. The inhibitor of apoptosis protein family has eight members and plays an important role in apoptosis, with the most studied being survivin (BIRC5) and Xlinked inhibitor of apoptosis (XIAP). YM155 is a small molecule with antineoplastic potential that has been described as a suppressant of survivin and XIAP. In the present study, BIRC5 expression was significantly increased in primary myelofibrosis patients compared to healthy donors. On the other hand, XIAP expression was reduced in myeloproliferative neoplasms patients. In JAK2 V617F cells, YM155 reduces cell viability and autonomous clonal growth and induces apoptosis, cell cycle arrest, and autophagy. HEL cells that show greater malignancy are more sensitive to the drug than SET2 cells. In the molecular scenario, YM155 modulates apoptosis-, cell cycle-, DNA damage- and autophagy-related genes. Protein expression analysis corroborates the observed cellular phenotype and exploratory gene expression findings. In summary, our results indicate that survivin/BIRC5 and XIAP are differently expressed in myeloproliferative neoplasms and YM155 has multiple antineoplastic effects on JAK2 V617F cells suggesting that inhibitor of apoptosis proteins may be a target for pharmacological interventions in the treatment of these diseases. (c) 2024 Associa & ccedil;& atilde;o Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Espa & ntilde;a, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). (AU)

• Processo FAPESP: 21/11606-3 - Investigação dos efeitos antineoplásicos de novos inibidores de PIP4K2 e HDAC em neoplasias hematológicas
• Beneficiário: João Agostinho Machado Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/12842-0 - Impacto da ancestralidade genética no desenvolvimento, características moleculares e desfecho clínico em pacientes adultos com Leucemia Linfoblástica Aguda
• Beneficiário: Keli Cristina de Lima
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 21/06138-0 - Caracterização da atividade de potenciais inibidores de histona desacetilase (HDAC) em modelos pré-clínicos de neoplasias hematólogicas
• Beneficiário: Jorge Antonio Elias Godoy Carlos
• Modalidade de apoio: Bolsas no Brasil - Doutorado