Precursor B-ALL cell lines differentially respond to syk inhibition by entospletinib
Creators: name: Sender, Sina
name: Sekora, Anett
name: Perez, Simon V.
name: Chabanovska, Oleksandra
name: Becker, Annegret
name: Ngezahayo, Anaclet
name: Junghanss, Christian
name: Murua Escobar, Hugo
Publisher: name: Basel : MDPI
Year: 2021
Subjects: subject: Acute lymphoblastic leukemia
subject: B-ALL
subject: BCR
subject: Ento
subject: Entospletinib
subject: Expression analysis
subject: GS-9973
subject: Pathway-specific inhibitors
subject: SYK
subject: B lymphocyte receptor
subject: entospletinib
subject: glycogen synthase kinase 3beta
subject: mitogen activated protein kinase
subject: protein bcl 6
subject: protein kinase B
subject: protein kinase Syk
subject: protein p53
subject: 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine
subject: indazole derivative
subject: pyrazine derivative
subject: SYK protein, human
subject: acute B-cell leukemia cell line
subject: antiproliferative activity
subject: apoptosis
subject: cell cycle
subject: cell metabolism
subject: cell proliferation
subject: controlled study
subject: flow cytometry
subject: gene expression
subject: human
subject: human cell
subject: immunofluorescence
subject: NALM-6 cell line
subject: proapoptotic activity
subject: protein analysis
subject: protein expression
subject: RNA sequencing
subject: RS4 11 cell line
subject: SEM cell line
subject: SU-DHL-4 cell line
subject: SUP-T1 cell line
subject: Western blotting
subject: acute lymphoblastic leukemia
subject: drug effect
subject: gene expression regulation
subject: genetics
subject: metabolism
subject: pathology
subject: pre B lymphocyte
subject: sequence analysis
subject: tumor cell line
subject: Apoptosis
subject: Cell Cycle
subject: Cell Line, Tumor
subject: Cell Proliferation
subject: Flow Cytometry
subject: Gene Expression Regulation, Leukemic
subject: Humans
subject: Indazoles
subject: Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
subject: Precursor Cells, B-Lymphoid
subject: Pyrazines
subject: Sequence Analysis, RNA
subject: Syk Kinase
subject: Dewey Decimal Classification::500 | Naturwissenschaften::570 | Biowissenschaften, Biologie
subject: Dewey Decimal Classification::500 | Naturwissenschaften::540 | Chemie

description: 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.