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Sci Rep ; 14(1): 23882, 2024 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-39396074

RESUMO

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.


Assuntos
Autofagia , Inflamassomos , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Autofagia/efeitos dos fármacos , Inflamassomos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Feminino , Masculino , Benzotiazóis/farmacologia , Pessoa de Meia-Idade , Sorafenibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Idoso , Compostos de Fenilureia
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