| Texto completo | |
| Autor(es): Mostrar menos - |
Lima, Keli
;
Pereira-Martins, Diego Antonio
;
Lins de Miranda, Livia Bassani
;
Coelho-Silva, Juan Luiz
;
Leandro, Giovana da Silva
;
Weinhauser, Isabel
;
Cavaglieri, Rita de Cassia
;
Leal, Aline de Medeiros
;
da Silva, Wellington Fernandes
;
Alencar de Lima Lange, Ana Paula
;
Rodrigues Pereira Velloso, Elvira Deolinda
;
Griessinger, Emmanuel
;
Hilberink, Jacobien R.
;
Ammatuna, Emanuele
;
Huls, Gerwin
;
Schuringa, Jan Jacob
;
Rego, Eduardo Magalhaes
;
Machado-Neto, Joao Agostinho
Número total de Autores: 18
|
| Tipo de documento: | Artigo Científico |
| Fonte: | BLOOD CANCER JOURNAL; v. 12, n. 11, p. 11-pg., 2022-11-09. |
| Resumo | |
The treatment of acute leukemia is challenging because of the genetic heterogeneity between and within patients. Leukemic stem cells (LSCs) are relatively drug-resistant and frequently relapse. Their plasticity and capacity to adapt to extracellular stress, in which mitochondrial metabolism and autophagy play important roles, further complicates treatment. Genetic models of phosphatidylinositol-5-phosphate 4-kinase type 2 protein (PIP4K2s) inhibition have demonstrated the relevance of these enzymes in mitochondrial homeostasis and autophagic flux. Here, we uncovered the cellular and molecular effects of THZ-P1-2, a pan-inhibitor of PIP4K2s, in acute leukemia cells. THZ-P1-2 reduced cell viability and induced DNA damage, apoptosis, loss of mitochondrial membrane potential, and the accumulation of acidic vesicular organelles. Protein expression analysis revealed that THZ-P1-2 impaired autophagic flux. In addition, THZ-P1-2 induced cell differentiation and showed synergistic effects with venetoclax. In primary leukemia cells, LC-MS/MS-based proteome analysis revealed that sensitivity to THZ-P1-2 is associated with mitochondrial metabolism, cell cycle, cell-of-origin (hematopoietic stem cell and myeloid progenitor), and the TP53 pathway. The minimal effects of THZ-P1-2 observed in healthy CD34(+) cells suggest a favorable therapeutic window. Our study provides insights into the pharmacological inhibition of PIP4K2s targeting mitochondrial homeostasis and autophagy, shedding light on a new class of drugs for acute leukemia. (AU) | |
| Processo FAPESP: | 15/09228-0 - Detecção e estudo funcional de Macrofágos Associados a Tumor em um modelo transgênico de leucemia promielocítica aguda. |
| Beneficiário: | Isabel Weinhauser |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| 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: | 19/23864-7 - Análise compreensiva de dados genômicos para identificação e validação de novos alvos terapêuticos envolvidos na regulação de citoesqueleto celular em Leucemias agudas |
| Beneficiário: | João Agostinho Machado Neto |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| 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: | 17/23117-1 - Avaliação da via TP53/TP73 na enxertia de células de leucemia promielocítica aguda em modelo de xenotransplante |
| Beneficiário: | Diego Antonio Pereira Martins |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |