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Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib.

ABSTRACT: 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. 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. 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, pGSK3β, p53 and BCL-6, were affected by Ento exposure in the inhibitor-sensitive cell lines. 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.

SUBMITTER: Sender S

PROVIDER: S-EPMC7827334 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib.

Sender Sina S Sekora Anett A Villa Perez Simon S Chabanovska Oleksandra O Becker Annegret A Ngezahayo Anaclet A Junghanss Christian C Murua Escobar Hugo H

International journal of molecular sciences 20210108 2

<h4>Background</h4>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 t ...[more]

PMID: 33435587

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Dataset Information

Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib.

Publications

Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib.

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