Better understanding of the biology of resistance to DNA methyltransferase (DNMT) inhibitors (DNMTi) is required to identify therapies that can improve their efficacy for patients with highrisk myelodysplastic syndrome (MDS). CCRL2 is an atypical chemokine receptor that is upregulated in CD34+ cells from MDS patients and induces MDS and secondary AML (sAML) cell proliferation. In this study, we evaluated any role CCRL2 may have in the regulation of pathways associated with poor response or resistance to DNMTi. We found that CCRL2 KD in TF-1 cells downregulates DNA methylation and PRC2 activity pathways and increases DNA methyltransferases (DNMT) suppression by azacitidine in MDS/sAML vell lines (MDS92, MDS-L and TF-1). Consistently, CCRL2 deletion increased the sensitivity of these cells to azacitidine in vitro and the efficacy of azacitidine in an MDS-L xenograft model. Consistently, CCRL2 overexpression in MDS-L and TF-1 cells decreased their sensitivity to azacitidine. Finally, CCRL2 levels were higher in CD34+ cells from MDS and MDS/myeloproliferative neoplasm patients with poor response to DNMTi. In conclusion, we demonstrate that CCRL2 modulates epigenetic regulatory pathways, particularly DNMT levels, and affects MDS/sAML azacitidine sensitivity. These results support CCRL2 targeting as having MDS/sAML therapeutic potential.
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