Journal article

Publication year: 2017

Pages: 2491-2502

Journal: Leukemia

Volume number: 31

Issue number: 11

ISSN: 0887-6924

eISSN: 1476-5551

Open access status: Hybrid

DOI Link: https://doi.org/10.1038/leu.2017.105

Publisher: Springer Nature [academic journals on nature.com]

Abstract: 
The AML1/Runx1 transcription factor and its heterodimerization partner CBF beta 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 CBF beta 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/CBF beta interaction (AE9aNT). We report that the AE9a/CBF beta 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 CBF beta. 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.

Harvard Citation style: Thiel, V., Giaimo, B., Schwarz, P., Soller, K., Vas, V., Bartkuhn, M., et al. (2017) Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation, Leukemia, 31(11), pp. 2491-2502. https://doi.org/10.1038/leu.2017.105

APA Citation style: Thiel, V., Giaimo, B., Schwarz, P., Soller, K., Vas, V., Bartkuhn, M., Blätte, T., Döhner, K., Bullinger, L., Borggrefe, T., Geiger, H., & Oswald, F. (2017). Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation. Leukemia. 31(11), 2491-2502. https://doi.org/10.1038/leu.2017.105