Bitte benutzen Sie diese Referenz, um auf diese Ressource zu verweisen:
doi:10.22028/D291-42769
Titel: | Targeting MYC in combination with epigenetic regulators induces synergistic anti-leukemic effects in MLLr leukemia and simultaneously improves immunity |
VerfasserIn: | Fitzel, Rahel Secker-Grob, Kathy-Ann Keppeler, Hildegard Korkmaz, Fulya Schairer, Rebekka Erkner, Estelle Schneidawind, Dominik Lengerke, Claudia Hentrich, Thomas Schulze-Hentrich, Julia M. Schneidawind, Corina |
Sprache: | Englisch |
Titel: | Neoplasia |
Bandnummer: | 41 |
Verlag/Plattform: | Elsevier |
Erscheinungsjahr: | 2023 |
Freie Schlagwörter: | MLL-rearranged leukemia MYC MAT2A CRISPR/Cas9 Immune defense |
DDC-Sachgruppe: | 500 Naturwissenschaften |
Dokumenttyp: | Journalartikel / Zeitschriftenartikel |
Abstract: | MLL rearranged (MLLr) leukemias are associated with a poor prognosis and a limited response to conventional therapies. Moreover, chemotherapies result in severe side effects with significant impairment of the immune system. Therefore, the identification of novel treatment strategies is mandatory. Recently, we developed a human MLLr leukemia model by inducing chromosomal rearrangements in CD34+ cells using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9. This MLLr model authentically mimics patient leukemic cells and can be used as a platform for novel treatment strategies. RNA sequencing of our model revealed MYC as one of the most important key drivers to promote oncogenesis. However, in clinical trials the BRD4 inhibitor JQ-1 leading to indirect blocking of the MYC pathway shows only modest activity. We and others previously reported that epigenetic drugs targeting MAT2A or PRMT5 promote cell death in MLLr cells. Therefore, we use these drugs in combination with JQ-1 leading to augmented anti-leukemic effects. Moreover, we found activation of T, NK and iNKT cells, release of immunomodulatory cytokines and downregulation of the PD-1/PD-L1 axis upon inhibitor treatment leading to improved cytotoxicity. In summary, the inhibition of MYC and MAT2A or PRMT5 drives robust synergistic anti-leukemic activity in MLLr leukemia. Moreover, the immune system is concomitantly activated upon combinatorial inhibitor treatment, hereby further augmenting the therapeutic efficiency. |
DOI der Erstveröffentlichung: | 10.1016/j.neo.2023.100902 |
URL der Erstveröffentlichung: | https://doi.org/10.1016/j.neo.2023.100902 |
Link zu diesem Datensatz: | urn:nbn:de:bsz:291--ds-427697 hdl:20.500.11880/38356 http://dx.doi.org/10.22028/D291-42769 |
ISSN: | 1476-5586 |
Datum des Eintrags: | 5-Sep-2024 |
Fakultät: | NT - Naturwissenschaftlich- Technische Fakultät |
Fachrichtung: | NT - Biowissenschaften |
Professur: | NT - Prof. Dr. Julia Schulze-Hentrich |
Sammlung: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
Dateien zu diesem Datensatz:
Datei | Beschreibung | Größe | Format | |
---|---|---|---|---|
1-s2.0-S1476558623000271-main.pdf | 2,2 MB | Adobe PDF | Öffnen/Anzeigen |
Diese Ressource wurde unter folgender Copyright-Bestimmung veröffentlicht: Lizenz von Creative Commons