TY - JOUR
T1 - Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia
AU - Meldi, Kristen
AU - Qin, Tingting
AU - Buchi, Francesca
AU - Droin, Nathalie
AU - Sotzen, Jason
AU - Micol, Jean Baptiste
AU - Selimoglu-Buet, Dorothée
AU - Masala, Erico
AU - Allione, Bernardino
AU - Gioia, Daniela
AU - Poloni, Antonella
AU - Lunghi, Monia
AU - Solary, Eric
AU - Abdel-Wahab, Omar
AU - Santini, Valeria
AU - Figueroa, Maria E.
N1 - Publisher Copyright:
© 2015, American Society for Clinical Investigation. All rights reserved.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding 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. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next-generation sequencing. These DMRs were primarily localized to nonpromoter 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 differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34+ and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance.
AB - Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding 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. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next-generation sequencing. These DMRs were primarily localized to nonpromoter 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 differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34+ and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance.
UR - http://www.scopus.com/inward/record.url?scp=84928982643&partnerID=8YFLogxK
U2 - 10.1172/JCI78752
DO - 10.1172/JCI78752
M3 - Article
C2 - 25822018
AN - SCOPUS:84928982643
SN - 0021-9738
VL - 125
SP - 1857
EP - 1872
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -