1. Precursor B-ALL Cell Lines Differentially Respond to SYK Inhibition by Entospletinib.
- Author
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Sender S, Sekora A, Villa Perez S, Chabanovska O, Becker A, Ngezahayo A, Junghanss C, and Murua Escobar H
- Subjects
- Apoptosis genetics, Cell Cycle drug effects, Cell Cycle genetics, Cell Line, Tumor, Cell Proliferation genetics, Flow Cytometry methods, Gene Expression Regulation, Leukemic drug effects, Humans, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma pathology, Precursor Cells, B-Lymphoid metabolism, Precursor Cells, B-Lymphoid pathology, Sequence Analysis, RNA methods, Syk Kinase genetics, Syk Kinase metabolism, Apoptosis drug effects, Cell Proliferation drug effects, Indazoles pharmacology, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cells, B-Lymphoid drug effects, Pyrazines pharmacology, Syk Kinase antagonists & inhibitors
- 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, pGSK3β, 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.
- Published
- 2021
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