Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation

[thumbnail of Original Article]
Preview
PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
5MB
[thumbnail of Supplemental Information] Other (Supplemental Information)
10MB

Item Type:Article
Title:Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation
Creators Name:Thiel, V.N., Giaimo, B.D., Schwarz, P., Soller, K., Vas, V., Bartkuhn, M., Blätte, T.J., Döhner, K., Bullinger, L., Borggrefe, T., Geiger, H. and Oswald, F.
Abstract:The AML1/Runx1 transcription factor and its heterodimerization partner CBFβ are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFβ in AE-mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia-initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFβ interaction (AE9aNT). We report that the AE9a/CBFβ interaction is not required for the AE9a-mediated aberrant expression of AML1 target genes, while upregulation/derepression of Notch target genes does require the interaction with CBFβ. Using retroviral transduction to express AE9a in murine adult bone marrow-derived hematopoietic progenitors, we observed that both AE9a and AE9aNT lead to increased myeloproliferation in vivo. However, both development of leukemia and long-term replating capacity are only observed with AE9a but not with AE9aNT. Thus, deregulation of both AML1 and Notch target genes is required for the development of AE9a-driven leukemia.
Keywords:Cell Differentiation, Cell Line, Core Binding Factor Alpha 2 Subunit, Core Binding Factor beta Subunit, Dimerization, Fusion Oncogene Proteins, Inbred C57BL Mice, Leukemia, RUNX1 Translocation Partner 1 Protein, Animals, Mice
Source:Leukemia
ISSN:1476-5551
Publisher:Springer Nature
Volume:31
Number:11
Page Range:2491-2502
Date:November 2017
Official Publication:https://doi.org/10.1038/leu.2017.105
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library