Investigating the response of paediatric leukaemia-propagating cells to BCL-2 inhibitors.
Br J Haematol
; 192(3): 577-588, 2021 02.
Article
en En
| MEDLINE
| ID: mdl-32452017
ABSTRACT
Relapse of paediatric acute lymphoblastic leukaemia (ALL) may occur due to persistence of resistant cells with leukaemia-propagating ability (LPC). In leukaemia, the balance of B-cell lymphoma-2 (BCL-2) family proteins is disrupted, promoting survival of malignant cells and possibly LPC. A direct comparison of BCL-2 inhibitors, navitoclax and venetoclax, was undertaken on LPC subpopulations from B-cell precursor (BCP) and T-cell ALL (T-ALL) cases in vitro and in vivo. Responses were compared to BCL-2 levels detected by microarray analyses and Western blotting. In vitro, both drugs were effective against most BCP-ALL LPC, except CD34- /CD19- cells. In contrast, only navitoclax was effective in T-ALL and CD34- /CD7- LPC were resistant to both drugs. In vivo, navitoclax was more effective than venetoclax, significantly improving survival of mice engrafted with BCP- and T-ALL samples. Venetoclax was not particularly effective against T-ALL cases in vivo. The proportions of CD34+ /CD19- , CD34- /CD19- BCP-ALL cells and CD34- /CD7- T-ALL cells increased significantly following in vivo treatment. Expression of pro-apoptotic BCL-2 genes was lower in these subpopulations, which may explain the lack of sensitivity. These data demonstrate that some LPC were resistant to BCL-2 inhibitors and sustained remission will require their use in combination with other therapeutics.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Leucemia-Linfoma Linfoblástico de Células Precursoras B
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Compuestos Bicíclicos Heterocíclicos con Puentes
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Proteínas Proto-Oncogénicas c-bcl-2
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Leucemia-Linfoma Linfoblástico de Células T Precursoras
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Compuestos de Anilina
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Antineoplásicos
Límite:
Adolescent
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Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
Br J Haematol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Reino Unido
Pais de publicación:
ENGLAND
/
ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
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REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM