Haematologica (Dec 2022)

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

DOI
https://doi.org/10.3324/haematol.2022.281444
Journal volume & issue
Vol. 108, no. 7

Abstract

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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.