Abstract
Allogeneic stem cell transplantation is currently the only curative treatment option for myelodysplastic syndromes (MDS). Pre-transplant debulking treatment have been employed for advanced MDS and we previously reported that marrow response (blast ≤ 5%) following the bridging therapy with hypomethylating agent was an independent favorable factor for survival; however, it is still not clear which patients will respond to hypomethylating agent and which genomic features can predict the response. In this study, we performed RNAseq for 23 MDS patients among which 14 (61%) and 9 (39%) patients showed marrow complete remission and primary resistance to azacitidine, respectively. Differential expression-based analyses of treatment-naive, baseline gene expression profiles revealed that molecular functions representing mitochondria and apoptosis were up-regulated in responders. In contrast, we identified genes involved in the Wnt pathway were relatively up-regulated in non-responders. In independent validation cohorts of MDS patients, the expression of gene sets specific to non-responders and responders distinguished the patients with favorable prognosis and those responded to azacitidine highlighting the prognostic and predictive implication. In addition, a systems biology approach identified genes involved in ubiquitination, such as UBC and PFDN2, which may be key players in the regulation of differential gene expression in treatment responders and non-responders. Taken together, identifying the gene expression signature may advance our understanding of the molecular mechanisms of azacitidine and may also serve to predict patient responses to drug treatment.
Highlights
Allogeneic stem cell transplantation is currently the only curative treatment option for myelodysplastic syndromes (MDS)
hypomethylating agent (HMA) response in MDS is known to be associated with better survival both in transplant and nontransplant settings12,30,40, it has not been possible to clearly identify which patients will respond to drug therapy
The differentially expressed genes (DEGs) identified in this study were 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
Summary
Allogeneic stem cell transplantation is currently the only curative treatment option for myelodysplastic syndromes (MDS). Progression; there is no single gene that appears to be sufficient to elicit disease and the majority of genes mutated in MDS are present in fewer than 5% of cases, highlighting the complexity of the disease7,8 These heterogenity of MDS have led to the development of risk-based stratification systems, and treatment options such as hypomethylating agent (HMA) or allogeneic stem cell transplantation (SCT) are selected systematically according to risk groups. Associations between repressed expression of anti- DNMT1 miRNAs and HMA resistance have been noted24 All of these findings have contributed substantially to a better understanding of individual variability in HMA responses among MDS patients; mutation, methylation, or expression information involving limited genes are not full enough to understand disease heterogeneity with respect to different response to HMA treatment. In light of our findings and those of another study in which a positive correlation between marrow clearance and genomic mutations was reported, we aimed to identify the molecular markers that could predict a patient’s marrow response to HMA
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