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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

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