Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.

• MeSH
• apoptóza MeSH
• genový knockdown MeSH
• glioblastom genetika   patologie   MeSH
• HEK293 buňky MeSH
• heterografty MeSH
• ionizující záření MeSH
• kontrolní body buněčného cyklu MeSH
• lidé MeSH
• malá interferující RNA genetika   MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky * patologie   MeSH
• nádory mozku genetika   MeSH
• nestabilita genomu * MeSH
• oprava DNA * MeSH
• protein BRCA1 MeSH
• regulace genové exprese u nádorů MeSH
• tolerance záření MeSH
• transkripční faktory genetika   metabolismus   MeSH
• transkriptom MeSH
• umlčování genů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Xenograft models represent a promising tool to study the pathogenesis of hematological malignancies. To establish a reliable and appropriate in vivo model of aggressive human B-cell leukemia and lymphoma we xenotransplanted four p53-mutated cell lines and one ATM-mutated cell line into immunodeficient NOD/SCID IL2Rγ-null mice. The cell lines MEC-1, SU-DHL-4, JEKO-1, REC-1, and GRANTA-519 were transplanted intraperitoneally or subcutaneously and the engraftment was investigated using immunohistochemistry and flow cytometry. We found significant differences in engraftment efficiency. MEC-1, JEKO-1 and GRANTA-519 cell lines engrafted most efficiently, while SU-DHL-4 cells did not engraft at all. MEC-1 and GRANTA-519 massively infiltrated organs and the whole intraperitoneal cavity showing very aggressive growth. In addition, GRANTA-519 cells massively migrated to the bone marrow regardless of the transplantation route. The MEC-1 and GRANTA-519 cells can be especially recommended for in vivo study of p53-mutated chronic lymphocytic leukemia and ATM-mutated mantle cell lymphoma, respectively.

• MeSH
• ATM protein genetika   MeSH
• biologické markery MeSH
• chronická lymfatická leukemie genetika   metabolismus   patologie   MeSH
• genový knockout MeSH
• heterografty MeSH
• lidé MeSH
• lymfom z plášťových buněk genetika   patologie   MeSH
• modely nemocí na zvířatech MeSH
• mutace * MeSH
• myši inbrední NOD MeSH
• myši knockoutované MeSH
• myši SCID MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   MeSH
• receptory interleukinů - společná gama-podjednotka genetika   MeSH
• transplantace heterologní MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH