Dokument: Linker histone variant H1-0 dysregulation in ETV6::RUNX1+ preleukemia and B cell acute lymphoblastic leukemia
| Titel: | Linker histone variant H1-0 dysregulation in ETV6::RUNX1+ preleukemia and B cell acute lymphoblastic leukemia | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=68891 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20250310-155610-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Jepsen, Vera Helena [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Borkhardt, Arndt [Gutachter] Prof. Dr. Wesselborg, Sebastian [Gutachter] | |||||||
| Dokumententyp (erweitert): | Dissertation | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | The chromosomal translocation t(12;21)(p13;q22) gives rise to ETV6::RUNX1, the most common oncogenic fusion gene in pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). ETV6::RUNX1 arises before birth at high frequency and induces a clinically silent state that can persist for over a decade. In <1% of carriers, these preleukemic cells acquire secondary mutations that induce transformation to overt leukemia. The mechanisms contributing to quiescence of ETV6::RUNX1+ preleukemic cells still remain elusive. In this thesis, factors involved in ETV6::RUNX1+ preleukemia are characterized by generating CRISPR/Cas9-edited human induced pluripotent stem cell (hiPSC) models. These preleukemic hiPSC models express ETV6::RUNX1 at physiological levels via the endogenous ETV6 promoter. Transcriptional analyses identified upregulation of linker histone H1-0 at the ETV6::RUNX1+ preleukemic state, both in hiPSCs and during early B lymphoid differentiation. Moreover, publicly available expression data of 3,026 leukemia patient samples showed significantly elevated H1-0 levels in ETV6::RUNX1+ BCP-ALL compared to other leukemia entities. Dual-luciferase promoter assays revealed that H1-0 promoter activity can be induced by ETV6::RUNX1, but not by RUNX1. While chromatin immunoprecipitation assays did not indicate direct binding of ETV6::RUNX1 to the H1-0 promoter, H1-0 expression might be indirectly regulated via DNA methylation of a CpG island shore element or histone acetylation. Depletion of H1-0 via RNA interference affected epigenetic processes and inhibited ETV6::RUNX1 signature genes, including RAG1 and EPOR, indicating a key role of H1-0 in regulating the ETV6::RUNX1 transcriptome. Analysis of single-cell sequencing data showed that H1-0 is highly expressed in quiescent hematopoietic cells. H1-0 expression can be induced in BCP-ALL cell lines by addition of histone deacetylase inhibitors (HDACis) and H1-0 protein levels correspond to susceptibility towards this drug class. Following up on these findings, combinatorial drug treatments using the H1-0-inducing HDACi Quisinostat were performed. These experiments showed promising synergism of Quisinostat with established chemotherapeutic drugs used for B-ALL treatment and the proteasome inhibitor Bortezomib in ETV6::RUNX1+ cells. Taken together, these data identify H1-0 as a key regulator of the ETV6::RUNX1+ transcriptome and indicate that induction of H1-0 via HDACis might be a potential novel approach to improve ETV6::RUNX1+ BCP-ALL treatment. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 10.03.2025 | |||||||
| Dateien geändert am: | 10.03.2025 | |||||||
| Promotionsantrag am: | 03.09.2024 | |||||||
| Datum der Promotion: | 24.01.2025 |
