title: Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia.
abstract: 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.
authors.forename: Kristen
authors.initials: K
authors.lastname: Meldi
authors.forename: Tingting
authors.initials: T
authors.lastname: Qin
authors.forename: Francesca
authors.initials: F
authors.lastname: Buchi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.forename: Jason
authors.initials: J
authors.lastname: Sotzen
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Micol
authors.forename: Dorothée
authors.initials: D
authors.lastname: Selimoglu-Buet
authors.forename: Erico
authors.initials: E
authors.lastname: Masala
authors.forename: Bernardino
authors.initials: B
authors.lastname: Allione
authors.forename: Daniela
authors.initials: D
authors.lastname: Gioia
authors.forename: Antonella
authors.initials: A
authors.lastname: Poloni
authors.forename: Monia
authors.initials: M
authors.lastname: Lunghi
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Valeria
authors.initials: V
authors.lastname: Santini
authors.forename: Maria E
authors.initials: ME
authors.lastname: Figueroa
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D001853:Bone Marrow / Q000473:pathology; D019175:DNA Methylation / Q000187:drug effects; D004252:DNA Mutational Analysis; D021901:DNA, Intergenic / Q000235:genetics; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D052138:Genes, Neoplasm; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D010978:Platelet Factor 4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016896:Treatment Outcome; D001620:beta-Thromboglobulin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
chemical_list: D000964:Antimetabolites, Antineoplastic; D021901:DNA, Intergenic; D009363:Neoplasm Proteins; C061615:PPBP protein, human; D001620:beta-Thromboglobulin; D010978:Platelet Factor 4; D000077209:Decitabine; D001374:Azacitidine
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