The Role of 4-GES Gene Expression Signatures in AML Prognostics

A new suggests that the gene expression signature 4-GES, which consists of four genes (SOCS2, IL2RA, NPDC1, PHGDH), may be an independent prognostic factor in acute myeloid leukemia (AML). Writing in Scientific Reports, researchers report 4-GES is a highly significant independent prognostic parameter throughout several independent AML cohorts and it has a major advantage over previously published signatures because it is composed of only four genes.

Chi Huu Nguyen, with the Medical University of Vienna, Vienna, Austria and colleagues used four independent microarray data sets from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA). They found that 4-GES has the potential to refine the European Leukemia Net (ELN) classification by reassigning a substantial number of patients into the prognostically poor subgroup. Since this expression signature only includes four genes, the authors theorize it could be easily adopted in current clinical practice.

The investigation included a total of 1,272 patients and it showed an oncogenic role of the top scoring gene in the signature SOCS2. The researchers investigated SOCS2 using MLL-AF9 and Flt3-ITD/NPM1c driven mouse models of AML and found that it promoted leukemogenesis and the abundance, quiescence, and activity of AML stem cells. “The newly established role of SOCS2 in leukemia aggressiveness and stemness raises the possibility that the signature might even be exploitable therapeutically,” the authors wrote.

Daniel R Couriel, MD, MS, who is the Director of the Utah Blood and Marrow Transplant Program at the Huntsman Cancer Institute and a Professor of Medicine at the University of Utah, Salt Lake City, Utah, said medical decisions for treating AML are based on cytogenetic and molecular markers that are strongly predictive of better or worse outcome, and some molecular markers have improved risk-stratification for patients in the intermediate risk category. “Unfortunately, a substantial number of patients without these defining molecular changes still exist,” Dr. Couriel told Cancer Network. “In this study, 4-GES predicted patient survival as an independent prognostic parameter in several cohorts of AML patients and further refined prognostication based on the European Leukemia Net classification. The difference in survival outcomes was significant in the cytogenetic intermediate group (normal cytogenetics) and 4-GES was an independent prognostic marker in this setting.”

In the cytogenetically favorable and poor groups, 4-GES did not provide additional prognostic information, but the cytogenetically poor cohort was small in size. “Overall, I think this work provides significant contribution to the field of AML,” said Dr. Couriel. “The 4-GES may lead to further risk stratification of the still sizable intermediate risk AML group, facilitating crucial therapeutic decisions like the need for hematopoietic stem cell transplantation.”

In the current study, researchers established a new gene expression signature that was consistently associated with survival in seven cohorts of AML patients with publicly available gene expression and survival data. Previous studies have also shown oncogenic roles of SOCS2 in colon and prostate cancer. Derek Stirewalt, MD, a member of the Clinical Research Division at Fred Hutchinson Cancer Center in Seattle, Washington said these new findings are very promising and have the potential to improve outcomes in select patients with AML. “It is a well done study, it is interesting and promising and better than some of the other studies. They actually tried to compare their findings to some of the gold standards. They also looked at expression,” Dr. Stirewalt said in an interview with Cancer Network.

He said the study was hampered, however, because it used old ELN guidelines from 2010 and not the latest ones issued in 2017. Dr. Stirewalt noted that future studies will need to show whether this new 4-gene signature adds anything to the newer ELN guidelines from 2017. “Models miss about 30% of time, but if it were 5%, it would make a big difference. How much more accurate will this make it?  It is not clear yet from this study. This is very interesting. It needs to undergo additional testing and calibration with the gold standards. I think it potentially could change clinical practice, but much more additional work will need to be done,” said Dr. Stirewalt.
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References:

1)  Nguyen CH, Glüxam T, Schlerka A, et al. SOCS2 is part of a highly prognostic 4-gene signature in AML and promotes disease aggressiveness. Scientific Reports volume 9, Article number: 9139 (2019). https://www.nature.com/articles/s41598-019-45579-0