Article ; Online: Functional characterization of cooperating MGA mutations in RUNX1::RUNX1T1 acute myeloid leukemia.
2024 Volume 38, Issue 5, Page(s) 991–1002
Abstract: MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological ...
| Abstract | MGA (Max-gene associated) is a dual-specificity transcription factor that negatively regulates MYC-target genes to inhibit proliferation and promote differentiation. Loss-of-function mutations in MGA have been commonly identified in several hematological neoplasms, including acute myeloid leukemia (AML) with RUNX1::RUNX1T1, however, very little is known about the impact of these MGA alterations on normal hematopoiesis or disease progression. We show that representative MGA mutations identified in patient samples abolish protein-protein interactions and transcriptional activity. Using a series of human and mouse model systems, including a newly developed conditional knock-out mouse strain, we demonstrate that loss of MGA results in upregulation of MYC and E2F targets, cell cycle genes, mTOR signaling, and oxidative phosphorylation in normal hematopoietic cells, leading to enhanced proliferation. The loss of MGA induces an open chromatin state at promoters of genes involved in cell cycle and proliferation. RUNX1::RUNX1T1 expression in Mga-deficient murine hematopoietic cells leads to a more aggressive AML with a significantly shortened latency. These data show that MGA regulates multiple pro-proliferative pathways in hematopoietic cells and cooperates with the RUNX1::RUNX1T1 fusion oncoprotein to enhance leukemogenesis. |
|---|---|
| MeSH term(s) | Animals ; Core Binding Factor Alpha 2 Subunit/genetics ; Mice ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Humans ; RUNX1 Translocation Partner 1 Protein/genetics ; Mutation ; Transcription Factors/genetics ; Mice, Knockout ; Cell Proliferation ; Oncogene Proteins, Fusion/genetics ; Gene Expression Regulation, Leukemic ; DNA-Binding Proteins ; Proto-Oncogene Proteins |
| Chemical Substances | Core Binding Factor Alpha 2 Subunit ; RUNX1 Translocation Partner 1 Protein ; RUNX1 protein, human ; RUNX1T1 protein, human ; Transcription Factors ; Oncogene Proteins, Fusion ; MTG8 protein, mouse ; DNA-Binding Proteins ; Proto-Oncogene Proteins |
| Language | English |
| Publishing date | 2024-03-07 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural |
| ZDB-ID | 807030-1 |
| ISSN | 1476-5551 ; 0887-6924 |
| ISSN (online) | 1476-5551 |
| ISSN | 0887-6924 |
| DOI | 10.1038/s41375-024-02193-y |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 2295: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.