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Acute Myeloid Leukemia Regulatory Networks Identified

NEW YORK (GenomeWeb) – A University of Birmingham-led team has teased out interactions between key mutations in acute myeloid leukemia (AML) tumors and regulatory networks that may inform future treatments.

"In acute myeloid leukaemia, genes are targeted by mutations that encode either master regulators controlling cell identity or factors transmitting signals through the cell. Therefore the normal process of turning genes on or off is defunct," co-senior and co-corresponding author Constanze Bonifer, a cancer and genomic sciences researcher at the University of Birmingham, said in a statement. "When this happens, the cells step sideways from their normal developmental program and speed out of control." 

Through an integrated analysis of purified leukemic blast cells, Bonifer and her colleagues analyzed transcriptional networks in dozens of AML cases, along with the cis-regulatory element alterations coinciding with them. The findings, published online today in Nature Genetics, highlighted ties between transcriptomic and epigenomic features that correspond to specific transcription factor, signaling molecule, or nuclear protein gene mutations in AML.

"Crucially, AML cells from patients with the same types of mutations always take the same route when they head off in the wrong direction," Bonifer said. "Our analyses of each of the pathways that the cells took when developing into cancer identified key points in the cell that could be used in the future to target and develop new drugs to treat each type of AML in a different way."

She also noted that these mutational combinations are often present before treatment, but have never previously been identified in patients at diagnosis, "meaning that the cancer can later return as a different disease which is often more aggressive."

In an effort to build on results that members of the team published previously — including a Cancer Cell study out last month describing enhanced CCND2 expression in AML cases with oncogenic mutations in the RUNX1/ETO transcription factor — the researchers did transcriptomic analyses, chromatin conformation capture profiling, and digital footprinting in leukemic blast cells from AML cases with specific transcription factor or signaling gene mutations identified with targeted sequencing on 55 cancer-related genes.

In particular, the team incorporated RNA sequence data and open chromatin-mapping DNase I sequence from 29 purified leukemic blast samples from bone marrow or peripheral blood samples in AML cases involving a series of distinct mutations, including several distinct RUNX1 alterations.

Along with promoter cis-regulatory element interaction profiles and data for a dozen samples assessed with at least one genomic approach, the data revealed transcriptome, chromatin, transcription factor occupancy, and regulatory clusters that coincided with specific AML mutation subsets.

"Integrated analysis of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance," the authors wrote, adding that "identifying such alteration-specific pathways will offer an opportunity to eliminate their specific maintenance program by targeting multiple pathways simultaneously."