Their work may help to further understanding of the molecular mechanisms of hypomethylating agents (HMAs) and offer a guide for determining which patients are likely to respond to such treatment.
Through the use of next-generation transcriptome sequencing, researchers have singled out markers associated with response, or lack thereof, to hypomethylating agent (HMA) treatment among patients with myelodysplastic syndromes (MDS), which they then confirmed the potential prognostic and predictive value of in independent cohorts.
According to the researchers, their work can further understanding of the molecular mechanisms of HMAs and offer a guide for determining which patients are likely to respond to such treatment.
“For prediction, we first identified a set of [differentially expressed genes (DEGs)] that can segregate the AZA [azacitidine] responders and nonresponders,” explained the researchers. “The DEGs identified in this study were also able to group the patients from an independent MDS cohort into subgroups of distinguished drug response and overall survival, indicating the selected genes may potentially identify AZA responders and MDS patients with favorable or unfavorable prognosis.”
The researchers first sequenced 23 patients, 61% of which had a complete response to AZA and 39% who were refractory to treatment. In the 14 responders, the researchers observed molecular functions like cellular respiration and apoptosis, leading them to suggest that elevated expression of apoptosis-related genes at baseline may serve as an indicator of who will have favorable responses to AZA.
Meanwhile, genes involved in the Wnt pathway seemed to be upregulated in the 9 nonresponders. The researchers note that the upregulated expression of these pathway genes at baseline may encode cellular resistance to AZA.
According to the researchers, just 2 genes showed significantly different expression between the 2 groups: BAX and IFNG. Outside of these 2 genes, the researchers found no significant differences in FAS expression or between BCL2L10 and PLCB1 expression, both of which have previously been indicated as being expression markers of AZA sensitivity.
They then confirmed the validity of their findings by looking at the gene expression profiles of a separate cohort of patients. The patients in this independent cohort who had similar gene expressions to the responders in the study cohort also showed better survival than the patients in the independent cohort who had gene expression profiles mirroring the study’s nonresponders.
The researchers took a second independent cohort and labeled patients as “responder-like” or “nonresponder-like” based on the identified markers, which resulted in a prediction accuracy of 0.687.
“Thus, our gene markers may have both prognostic and predictive implication with the AZA treatment for MDS patients,” wrote the researchers, reflecting on their independent findings.
Kim K, Park S, Choi H, et al. Gene expression signatures associated with sensitivity to azacytidine in myelodysplastic syndromes. Sci Rep. Published online November 11, 2020. doi:10.1038/s41598-020-76510-7