Back to Search
Start Over
HoxA9 transforms murine myeloid cells by a feedback loop driving expression of key oncogenes and cell cycle control genes
- Source :
- Blood Advances; November 2018, Vol. 2 Issue: 22 p3137-3148, 12p
- Publication Year :
- 2018
-
Abstract
- Ectopic expression of the oncogenic transcription factor HoxA9 is a major cause of acute myeloid leukemia (AML). Here, we demonstrate that HoxA9 is a specific substrate of granule proteases. Protease knockout allowed the comprehensive determination of genome-wide HoxA9 binding sites by chromatin immunoprecipitation sequencing in primary murine cells and a human AML cell line. The kinetics of enhancer activity and transcription rates in response to alterations of an inducible HoxA9 were determined. This permitted identification of HoxA9-controlled enhancers and promoters, allocation to their respective transcription units, and discrimination against HoxA9-bound, but unresponsive, elements. HoxA9 triggered an elaborate positive-feedback loop that drove expression of the complete Hox-A locus. In addition, it controlled key oncogenic transcription factors Mycand Myband directly induced the cell cycle regulators Cdk6and CyclinD1, as well as telomerase, drawing the essential blueprint for perturbation of proliferation by leukemogenic HoxA9 expression.
Details
- Language :
- English
- ISSN :
- 24739529 and 24739537
- Volume :
- 2
- Issue :
- 22
- Database :
- Supplemental Index
- Journal :
- Blood Advances
- Publication Type :
- Periodical
- Accession number :
- ejs56961785
- Full Text :
- https://doi.org/10.1182/bloodadvances.2018025866