Site Editor

Rebecca Olin, MD, MS

Advertisement
Advertisement

AACR 2022: Therapeutic Potential of Targeting CCRL2 in Secondary AML

By: Vanessa A. Carter, BS
Posted: Wednesday, April 20, 2022

Theodoros Karantanos, MD, PhD, of Johns Hopkins University Hospital, Baltimore, and colleagues recently discovered that CCRL2—an atypical chemokine receptor—may promote the growth of myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML). Thus, they conducted a study to evaluate whether CCRL2 regulates pathways associated with resistance to hypomethylating agents in the treatment of MDS and AML. Presented during the American Association for Cancer Research (AACR) Annual Meeting 2022 (Abstract 5435), the results of this analysis suggest there is therapeutic potential in CCRL2 targeting.

“CCRL2 regulates the expression of genes associated with induction of PRC2-mediated histone modification and DNA methylation in secondary AML cells,” explained the study authors. “CCRL2 suppression also increased the sensitivity of MDS and secondary AML cells to azacitidine. In addition, increased CCRL2 expression in MDS cells is associated with worse response to hypomethylating agents.”

To suppress CCRL2 expression, lentivirus-mediated transduction of MDS (MDS-L), TF-1 MDS/secondary AML, and MDS92 cell lines were used; two different short-hairpin RNA constructs were used. Gene-set enrichment analysis and RNA sequencing of CCRL2 knock-down and wild-type TF-1 cells were performed. CD34-positive cells were collected from bone marrow of patients with MDS and measured for CCRL2.

The suppression of pathways associated with DNA methylation, histone modification, and PRC2 complex activity was observed in CCRL2 knock-down cells. Additionally, these cells appeared to display a more distinguished degradation of enzymes DNTM3B, DNMT3A, and DNMT1 when treated with azacitidine. In fact, apoptosis in response to azacitidine (P < .010) seemed to be increased by CCRL2.

Morphologic differentiation was increased by CCRL2 knock-down among treatment with azacitidine (P < .010); clonogenic inhibition caused by azacitidine was also increased (P < .05). The clinical effect of CCRL2 was evaluated by measuring its expression in CD34-positive cells from patients undergoing treatment with hypomethylating agents. Here, it was discovered that patients experiencing progressive disease expressed higher CCRL2 levels when compared with CD34-positive cells from individuals who responded to treatment (P = .020).

Disclosure: The study authors reported no conflicts of interest.


By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.