Specific molecular signatures underlie response to Decitabine in CMML

ABSTRACT: Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable with few means to predict which patients will benefit. To develop a molecular means of predicting response at diagnosis, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients responsive and resistant to Decitabine (DAC). While somatic mutations did not differentiate responders and non-responders, we were able to identify for the first time 167 differentially methylated regions (DMRs) at baseline between responders and non-responders using next-generation sequencing. These DMRs were primarily localized to non-promoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. Transcriptional analysis revealed that gene expression differences also exist at diagnosis between responders and non-responders. Genes up-regulated in responders were enriched in the cell cycle, potentially contributing to effective DAC incorporation. Two chemokines overexpressed in non-responders – CXCL4 and CXCL7 – were able to block the effect of DAC on normal CD34+ and primary CMML cells in vitro, suggesting their up-regulation contributes to primary DAC resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE63787 | GEO | 2017/08/29

SECONDARY ACCESSION(S): PRJNA269071

REPOSITORIES: GEO