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.
View: Text | PDF
Research Article Oncology

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

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

×

Figure 8

CXCL4 and CXCL7 promote resistance to DAC in CD34+ and primary CMML specimens.

Options: View larger image (or click on image) Download as PowerPoint
CXCL4 and CXCL7 promote resistance to DAC in CD34+ and primary CMML spec...
(A) Colony formation was inhibited by DAC but restored with the combination of CXCL4 and CXCL7. CD34+ cells were treated with 1 dose of CXCL4, CXCL7, or both (50 ng/ml each) or with vehicle (PBS containing 0.1% BSA) and daily 10-nM doses of DAC for 3 days. After 3 days of in vitro treatment with DAC, cells were plated in methylcellulose and incubated for 12 to 15 days before colonies were counted. Data represent the mean ± SD. Treatment with 10 nM DAC significantly decreased colony formation but failed to do so in the presence of CXCL7 and CXCL4 together. Shown in the 3 panels are the results of 3 independent experiments. Error bars represent the SD. (B) CXCL4 and CXCL7 abrogated the effect of DAC on the viability of primary CMML MNCs. CMML MNCs were treated in vitro for 72 hours with 10 nM DAC alone or in the presence of 50 ng/ml CXCL4, CXCL7, or both. Data represent the mean ± SD. Treatment with DAC alone significantly reduced the viability of these cells, but this effect was lost when CXCL4 or CXCL7 was added to the culture. All data represent independent experiments performed in 3 different CMML patients. Error bars represent the SD. *P < 0.05 and **P < 0.01 by unpaired 2-tailed Student’s t test.