Discovery of Subtype-Specific Transcriptional Regulators in AML Can Improve Personalized Treatment

A new study published in Nature Genetics suggests there may be new ways for personalized and precise treatment of acute myeloid leukemia (AML) that could increase the chances of survival in patients with this aggressive cancer of the white blood cells.

AML is made up of several groups of cells with different combinations of mutations, some of which are so aggressive they allow the cancer cells to survive after treatment. The different types of genetic alterations affect signaling pathways as well as transcriptional factors and epigenetic regulators. Mutations target genes that encode either master regulators that control cell identity or factors transmitting signals through the cell. Thus, in AML the normal process of turning genes on or off is dysfunctional.

When mutations occur, the cells retreat from their normal developmental program and speed out of control, Constanz Bonifer, PhD, the senior study author, explained in an associated press release. “Crucially, AML cells from patients with the same type of mutations always take the same route when they head off in the wrong direction.”

The researchers conducted a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy, and gene expression patterns in purified leukemic blast cells. They focused on specific subgroups of patients diagnosed with AML whose cells carry mutations in genes encoding transcription factors RUNX1 and CEBPα, signaling molecules FTL3-ITD, and RAS, and the nuclear protein NPM1.

Their analysis uncovered the basic mechanisms that regulate the production of these abnormal cells and identified the main trigger points and critical mutations in which affect other genes that control the cells’ identity and behavior. 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. Induced and aberrantly expressed transcription factors are not bystanders, the researchers conclude, but are important for network maintenance and leukemic growth. The AP-1 transcription factor family in particular—which plays an important role in many types of tumors—was found to play a major role in AML.

Bonifer explained that the mutations are often present before treatment, “but we have never previously been able to identify them when a patient is first diagnosed with AML—meaning that the cancer can later return as a different disease which is often more aggressive.” The new research makes it possible to identify these cells at diagnosis, allowing treatment with the right drug combination.

Peter Cockerill, PhD, the other senior author on the study, noted that patients with AML are already being tested for the many different mutations that cause AML, but now researchers know which genes are the most important for each type of AML. “This means that personalized medicine will one day become a reality for blood cell cancers, which will see a different drug being given to treat each form of AML, creating personalized treatment for each cancer patient depending on the mutation that has caused their disease.”

This research was funded by Bloodwise, a blood cancer research charity based in the United Kingdom.

Reference

Assi SA, Imperato MR, Coleman DJL, et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia [published online November 12, 2018]. Nat Genetics. doi: 10.1038/s41588-018-0270-1.