The AP-1 transcription factor family, important in many tumor types, plays a major role in acute myeloid leukemia, according to researchers who conducted a comprehensive global analysis of gene regulatory networks involved in this disease.
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This observation suggests new opportunities for targeted treatment of AML, according to the researchers, led by Peter N. Cockerill, PhD, and Constanze Bonifer, PhD, with the Institute of Cancer and Genomic Sciences, University of Birmingham, England.
“Induced and aberrantly expressed transcription factors are not bystanders, but are important for network maintenance and leukemic growth,” the investigators wrote in Nature Genetics.
Investigators combined data obtained via several different analytic techniques to construct transcription factor networks in normal CD34+ cells and cells from specific subgroups of subjects with defined mutations, including RUNX1 mutations, t(8;21) translocations, mutations of both alleles of the CEBPA gene, and FLT3-ITD with or without NPM1 mutation.
The AP-1 family network was of “high regulatory relevance” for all AML subtypes evaluated, the investigators reported.
Previous work revealed the existence of gene regulatory networks in different types of AML classified by gene expression and DNA-methylation patterns.
“Our work now defines these networks in detail, and shows that leukemic drivers determine the regulatory phenotype by establishing and maintaining specific gene regulatory and signaling networks that are distinct from those in normal cells,” the authors said in their report.
Follow-up in vitro and in vivo studies confirmed the importance of AP-1 for different AML subtypes.
In the in vitro study, investigators transduced AML cells with a doxycycline-inducible version of a dominant negative FOS protein.
“AP-1 is a heterodimer formed by members of the FOS, JUN, ATF, CREB and JDP families of transcription factors, thus it is challenging to target by defined RNA interference approaches,” the investigators explained.
Results of the in vitro study showed that induction of that protein, mediated by doxycycline, inhibited proliferation and colony-forming ability in AML cell lines.
To evaluate the relevance of AP-1 for leukemia propagation in vivo, they transplanted two different types of cells expressing inducible dominant negative FOS protein in immunodeficient mice.
For the first cell type, granulosarcomas developed in six out of seven mice in a control group, but in only two mice treated with doxycycline, neither of which expressed the inducible protein, suggesting that the transgene was silenced, according to the investigators. For the second cell type, doxycycline inhibited leukemia development, while untreated mice rapidly developed tumors.
“Taken together, these findings demonstrate the importance of AP-1 for several AML subtypes and emphasize the potential of transcriptional network analyses to predict transcription factors crucial for malignant propagation,” the investigators wrote.
They declared no competing interests related to their research, which was funded by Bloodwise, Cancer Research UK, a Kay Kendall Clinical Training Fellowship and a MRC/Leuka Clinical Training Fellowship.
SOURCE: Assi SA et al. Nat Genet. 2018 Nov 12. doi: 10.1038/s41588-018-0270-1.