CCRL2 affects the sensitivity of myelodysplastic syndrome and secondary acute myeloid leukemia cells to azacitidine
Theodoros Karantanos,
Patric Teodorescu,
Marios Arvanitis,
Brandy Perkins,
Tania Jain,
Amy E. DeZern,
W. Brian Dalton,
Ilias Christodoulou,
Bogdan C. Paun,
Ravi Varadhan,
Christopher Esteb,
Trivikram Rajkhowa,
Challice Bonifant,
Lukasz P. Gondek,
Mark J. Levis,
Srinivasan Yegnasubramanian,
Gabriel Ghiaur,
Richard J. Jones
Affiliations
Theodoros Karantanos
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Patric Teodorescu
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Marios Arvanitis
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore
Brandy Perkins
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Tania Jain
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Amy E. DeZern
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
W. Brian Dalton
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Ilias Christodoulou
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Bogdan C. Paun
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Ravi Varadhan
Division of Biostatistics and Bioinformatics, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Christopher Esteb
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Trivikram Rajkhowa
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Challice Bonifant
Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Lukasz P. Gondek
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Mark J. Levis
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Srinivasan Yegnasubramanian
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Gabriel Ghiaur
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Richard J. Jones
Division of Hematological Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore
Better understanding of the biology of resistance to DNA methyltransferase (DNMT) inhibitors is required to identify therapies that can improve their efficacy for patients with high-risk myelodysplastic syndrome (MDS). CCRL2 is an atypical chemokine receptor that is upregulated in CD34+ cells from MDS patients and induces proliferation of MDS and secondary acute myeloid leukemia (sAML) cells. In this study, we evaluated any role that CCRL2 may have in the regulation of pathways associated with poor response or resistance to DNMT inhibitors. We found that CCRL2 knockdown in TF-1 cells downregulated DNA methylation and PRC2 activity pathways and increased DNMT suppression by azacitidine in MDS/sAML cell 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. Furthermore, 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 DNMT inhibitors. In conclusion, we demonstrated that CCRL2 modulates epigenetic regulatory pathways, particularly DNMT levels, and affects the sensitivity of MDS/sAML cells to azacitidine. These results support CCRL2 targeting as having therapeutic potential in MDS/sAML.