HoxA9 transforms murine myeloid cells by a feedback loop driving expression of key oncogenes and cell cycle control genes.
Xiaoxia ZhongAndreas PrinzJulia StegerMaria-Paz Garcia-CuellarMarkus Philipp RadsakAbderrazzak BentaherRobert K SlanyPublished in: Blood advances (2019)
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 Myc and Myb and directly induced the cell cycle regulators Cdk6 and CyclinD1, as well as telomerase, drawing the essential blueprint for perturbation of proliferation by leukemogenic HoxA9 expression.
Keyphrases
- transcription factor
- cell cycle
- long non coding rna
- poor prognosis
- acute myeloid leukemia
- long noncoding rna
- genome wide
- genome wide identification
- cell proliferation
- dna binding
- induced apoptosis
- binding protein
- gene expression
- allogeneic hematopoietic stem cell transplantation
- cell cycle arrest
- endothelial cells
- dna methylation
- dendritic cells
- cell death
- oxidative stress
- immune response
- high glucose
- high resolution
- simultaneous determination
- diabetic rats
- amino acid