Zusammenfassung: | |
Background: Impaired B-cell receptor (BCR) function has been associated with the pro-gress 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, character-izing 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, apop-tosis 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. Ac-cordingly, SYK classifies as a potential target structure in a subset of pro-B-ALLs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Lizenzbestimmungen: | CC BY 4.0 Unported - https://creativecommons.org/licenses/by/4.0/ |
Publikationstyp: | Article |
Publikationsstatus: | publishedVersion |
Erstveröffentlichung: | 2021 |
Schlagwörter (englisch): | Acute lymphoblastic leukemia, B-ALL, BCR, Ento, Entospletinib, Expression analysis, GS-9973, Pathway-specific inhibitors, SYK, B lymphocyte receptor, entospletinib, glycogen synthase kinase 3beta, mitogen activated protein kinase, protein bcl 6, protein kinase B, protein kinase Syk, protein p53, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine, indazole derivative, protein kinase Syk, pyrazine derivative, SYK protein, human, acute B-cell leukemia cell line, antiproliferative activity, apoptosis, cell cycle, cell metabolism, cell proliferation, controlled study, flow cytometry, gene expression, human, human cell, immunofluorescence, NALM-6 cell line, proapoptotic activity, protein analysis, protein expression, RNA sequencing, RS4 11 cell line, SEM cell line, SU-DHL-4 cell line, SUP-T1 cell line, Western blotting, acute lymphoblastic leukemia, drug effect, gene expression regulation, genetics, metabolism, pathology, pre B lymphocyte, sequence analysis, tumor cell line, Apoptosis, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Flow Cytometry, Gene Expression Regulation, Leukemic, Humans, Indazoles, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Pyrazines, Sequence Analysis, RNA, Syk Kinase |
Fachliche Zuordnung (DDC): | 570 | Biowissenschaften, Biologie, 540 | Chemie |
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