All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL).
Eur J Haematol
; 104(3): 236-250, 2020 Mar.
Article
em En
| MEDLINE
| ID: mdl-31811682
ABSTRACT
OBJECTIVE:
In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all-trans-retinoic acid (ATRA) can restore retinoid-induced transcription and promote degradation of the PML-RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re-modeling. Recent studies have identified autophagy as an integral component of ATRA-induced myeloid differentiation.METHODS:
As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy-related transcripts.RESULTS:
ATRA altered the expression of >80 known autophagy-related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5-fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA-resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA.CONCLUSIONS:
We show for the first time that TFEB plays an important role in ATRA-induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note this study includes data obtained from NCT00195156, https//clinicaltrials.gov/show/NCT00195156).Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
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Leucemia
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Tratamento
/
Transplante_de_medula_ossea
Base de dados:
MEDLINE
Assunto principal:
Tretinoína
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Leucemia Promielocítica Aguda
/
Regulação Leucêmica da Expressão Gênica
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Diferenciação Celular
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Eur J Haematol
Assunto da revista:
HEMATOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Irlanda