Cyclosporine enhances the sensitivity to lenalidomide in MDS/AML in vitro

Abstract

Our previous study revealed that expression of G protein-coupled receptor 68 (GPR68) was upregulated in MDSL cells, a cell line representing myelodysplastic syndromes (MDS), in response to lenalidomide (LEN), and mediated a calcium/calpain proapoptotic pathway. Isx, a GPR68 agonist, enhanced the sensitivity to LEN in MDSL cells. The fact that Isx is not a U.S. Food and Drug Administration-approved drug prompts us to look for alternative candidates that could enhance the sensitivity of LEN in MDS as well as other hematologic malignancies, such as acute myeloid leukemia (AML). In the study described here, we found that regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of calcineurin (CaN), was upregulated in MDSL cells in response to LEN, possibly through degradation of IKZF1. Consistently, cyclosporin (Cys), a pharmacological inhibitor of CaN, inhibited the activity of CaN and induced apoptosis in MDSL cells, indicating that CaN provided a prosurvival signal in MDSL cells. In addition, Cys enhanced the cytotoxic effect of LEN in MDS/AML cell lines as well as primary bone marrow cells from MDS patients and AML patient-derived xenograft models. Intriguingly, pretreatment with LEN reversed the suppressive effect of Cys on T-cell activation. Our study suggests a novel mechanism of action of LEN in mediating cytotoxicity in MDS/AML via upregulation of RCAN1, thus inhibiting the CaN prosurvival pathway. Our study also suggests that Cys enhances the sensitivity to LEN in MDS/AML cells without compromising T-cell activation.

Pathogenic germline IKZF1 variant alters hematopoietic gene expression profiles

“…Lenalidomide has also been reported to induce IKZF1 degradation in low-risk del5q MDS (MDSL) cells, resulting in activation of a calcium/calpain proapoptotic pathway ( Fang et al 2016 ). Additionally, lenalidomide was recently reported to up-regulate Regulator of Calcineurin 1 ( RCAN1 ), which, in turn, suppressed calcineurin (CaN) ( He et al 2020 ). Depletion of IKZF1 in MDSL with siRNA increased RCAN1 mRNA ( He et al 2020 ).…”

“…Additionally, lenalidomide was recently reported to up-regulate Regulator of Calcineurin 1 ( RCAN1 ), which, in turn, suppressed calcineurin (CaN) ( He et al 2020 ). Depletion of IKZF1 in MDSL with siRNA increased RCAN1 mRNA ( He et al 2020 ). Future studies are required to understand whether variants in IKZF1 are associated with changes in this pathway.…”

Novel Molecular Mechanism of Lenalidomide in Myeloid Malignancies Independent of Deletion of Chromosome 5q

“…Haploinsufficiency of CSNK1A1 confers sensitivity to lenalidomide in del(5q) MDS [59]. Of note, we have identified targets of transcription repressor IKZF1 in MDS cells and acute myeloid leukemia (AML) cells, including G protein-coupled receptor 68 (GPR68) and regulator of calcineurin 1 (RCAN1) [61][62][63]. Delineation of the signaling pathways downstream of GPR68 and RCAN1 uncovers novel therapeutic targets that enhance the sensitivity to lenalidomide, especially in R/R and aggressive myeloid malignancies irrespective of del(5q).…”

“…Delineation of the signaling pathways downstream of GPR68 and RCAN1 uncovers novel therapeutic targets that enhance the sensitivity to lenalidomide, especially in R/R and aggressive myeloid malignancies irrespective of del(5q). A good example is Cyclosporin-A that inhibits the activity of calcineurin (CaN), a signaling molecule downstream of RCAN1 [62]. Cyclosporin-A enhances the sensitivity to lenalidomide in MDS/AML with or without del(5q).…”

“…Cyclosporin-A is an FDA-approved immunosuppressive drug that prevents rejection after organ transplantation [64]. Intriguingly, combined use of lenalidomide and Cyclosporin-A mediates strong tumoricidal effect on MDS/AML cells without damaging T cell function [62].…”