Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib.
Int J Mol Sci
; 22(2)2021 Jan 08.
Article
em En
| MEDLINE
| ID: mdl-33435587
ABSTRACT
BACKGROUND:
Impaired B-cell receptor (BCR) function has been associated with the progress of several B-cell malignancies. The spleen tyrosine kinase (SYK) represents a potential therapeutic target in a subset of B-cell neoplasias. In precursor B-acute lymphoblastic leukemia (B-ALL), the pathogenic role and therapeutic potential of SYK is still controversially discussed. We evaluate the application of the SYK inhibitor entospletinib (Ento) in pre- and pro-B-ALL cell lines, characterizing the biologic and molecular effects.METHODS:
SYK expression was characterized in pre-B-ALL (NALM-6) and pro-B-ALL cell lines (SEM and RS4;11). The cell lines were exposed to different Ento concentrations and the cell biological response analyzed by proliferation, metabolic activity, apoptosis induction, cell-cycle distribution and morphology. BCR pathway gene expression and protein modulations were further characterized.RESULTS:
Ento significantly induced anti-proliferative and pro-apoptotic effects in NALM-6 and SEM, while barely affecting RS4;11. Targeted RNAseq revealed pronounced gene expression modulation only in NALM-6, while Western Blot analyses demonstrated that vital downstream effector proteins, such as pAKT, pERK, pGSK3ß, p53 and BCL-6, were affected by Ento exposure in the inhibitor-sensitive cell lines.CONCLUSION:
Different acting modes of Ento, independent of pre-BCR dependency, were characterized, unexpected in SEM. Accordingly, SYK classifies as a potential target structure in a subset of pro-B-ALLs.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazinas
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Leucemia-Linfoma Linfoblástico de Células Precursoras B
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Apoptose
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Proliferação de Células
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Células Precursoras de Linfócitos B
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Quinase Syk
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Indazóis
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article