Identification of epigenetic modifiers essential for growth and survival of AML1/ETO-positive leukemia.
ATR
DNA methyltransferase
acute myeloid leukemia
epigenetic therapy
shRNA screen
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 Aug 2024
15 Aug 2024
Historique:
revised:
20
06
2024
received:
08
10
2023
accepted:
27
06
2024
medline:
15
8
2024
pubmed:
15
8
2024
entrez:
15
8
2024
Statut:
aheadofprint
Résumé
Aberrant gene expression patterns in acute myeloid leukemia (AML) with balanced chromosomal translocations are often associated with dysregulation of epigenetic modifiers. The AML1/ETO (RUNX1/MTG8) fusion protein, caused by the translocation (8;21)(q22;q22), leads to the epigenetic repression of its target genes. We aimed in this work to identify critical epigenetic modifiers, on which AML1/ETO-positive AML cells depend on for proliferation and survival using shRNA library screens and global transcriptomics approaches. Using shRNA library screens, we identified 41 commonly depleted genes in two AML1/ETO-positive cell lines Kasumi-1 and SKNO-1. We validated, genetically and pharmacologically, DNMT1 and ATR using several AML1/ETO-positive and negative cell lines. We also demonstrated in vivo differentiation of myeloblasts after treatment with the DNMT1 inhibitor decitabine in a patient with an AML1/ETO-positive AML. Bioinformatic analysis of global transcriptomics after AML1/ETO induction in 9/14/18-U937 cells identified 973 differentially expressed genes (DEGs). Three genes (PARP2, PRKCD, and SMARCA4) were both downregulated after AML1/ETO induction, and identified in shRNA screens. In conclusion, using unbiased shRNA library screens and global transcriptomics, we have identified several driver epigenetic regulators for proliferation in AML1/ETO-positive AML. DNMT1 and ATR were validated and are susceptible to pharmacological inhibition by small molecules showing promising preclinical and clinical efficacy.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Research Committee of the University of Freiburg
ID : DUQ1106/16
Organisme : ERA Per Med
ID : JTC 2018 GEPARD
Organisme : Berta Ottenstein-Program for Advanced Clinician Scientists, Faculty of Medicine, University of Freiburg
Organisme : Jose Carreras Leukemia Foundation
ID : R14/25
Organisme : Deutsche Forschungsgemeinschaft DFG
ID : DU 1287/5-1
Organisme : Deutsche Forschungsgemeinschaft DFG
ID : FOR 2674
Organisme : Deutsche Forschungsgemeinschaft DFG
ID : Project ID A05
Organisme : Deutsche Forschungsgemeinschaft DFG
ID : A09
Organisme : Deutsche Forschungsgemeinschaft DFG
ID : CRC 992 Medical Epi
Organisme : German Cancer Consortium DKTK
Informations de copyright
© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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