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Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia
Kristen Meldi, … , Valeria Santini, Maria E. Figueroa
Kristen Meldi, … , Valeria Santini, Maria E. Figueroa
Published March 30, 2015
Citation Information: J Clin Invest. 2015;125(5):1857-1872. https://doi.org/10.1172/JCI78752.
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Research Article Oncology Article has an altmetric score of 46

Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia

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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

Kristen Meldi, Tingting Qin, Francesca Buchi, Nathalie Droin, Jason Sotzen, Jean-Baptiste Micol, Dorothée Selimoglu-Buet, Erico Masala, Bernardino Allione, Daniela Gioia, Antonella Poloni, Monia Lunghi, Eric Solary, Omar Abdel-Wahab, Valeria Santini, Maria E. Figueroa

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Figure 7

CXCL4 and CXCL7 are upregulated in the BM of nonresponders.

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CXCL4 and CXCL7 are upregulated in the BM of nonresponders.
(A) qRT-PCR ...
(A) qRT-PCR showing validation of overexpression of CXCL4, CXCL7, and ITGB3 in nonresponders; each point represents the mean of triplicate wells for each patient sample; the line and error bars indicate the group mean and SD, respectively. (B) Pearson’s correlation analysis of expression levels of CXCL7 and CXCL4 by RNA-seq and qRT-PCR. (C and D) Representative IHC images for CXCL4 (C) and CXCL7 (D) in diagnostic BM biopsies in DAC responders and nonresponders. Original magnification, ×40 (C and D, left panels), ×63 (C and D, right panels). Representative images from duplicate experiments are shown.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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