UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia.
Genes Dev
; 30(5): 508-21, 2016 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-26944678
ABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of hematological tumors composed of distinct subtypes that vary in their genetic abnormalities, gene expression signatures, and prognoses. However, it remains unclear whether T-ALL subtypes differ at the functional level, and, as such, T-ALL treatments are uniformly applied across subtypes, leading to variable responses between patients. Here we reveal the existence of a subtype-specific epigenetic vulnerability in T-ALL by which a particular subgroup of T-ALL characterized by expression of the oncogenic transcription factor TAL1 is uniquely sensitive to variations in the dosage and activity of the histone 3 Lys27 (H3K27) demethylase UTX/KDM6A. Specifically, we identify UTX as a coactivator of TAL1 and show that it acts as a major regulator of the TAL1 leukemic gene expression program. Furthermore, we demonstrate that UTX, previously described as a tumor suppressor in T-ALL, is in fact a pro-oncogenic cofactor essential for leukemia maintenance in TAL1-positive (but not TAL1-negative) T-ALL. Exploiting this subtype-specific epigenetic vulnerability, we propose a novel therapeutic approach based on UTX inhibition through in vivo administration of an H3K27 demethylase inhibitor that efficiently kills TAL1-positive primary human leukemia. These findings provide the first opportunity to develop personalized epigenetic therapy for T-ALL patients.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Terapia Genética
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Regulação Neoplásica da Expressão Gênica
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Proteínas Proto-Oncogênicas
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Epigênese Genética
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Histona Desmetilases
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article