Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.
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PMID:A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes. 2738 82

GPR68 (or ovarian cancer G protein-coupled receptor 1, OGR1) is a proton-sensing G-protein-coupled receptor (GPCR) that responds to extracellular acidity and regulates a variety of cellular functions. Acidosis is considered a defining hallmark of the tumor microenvironment (TME). GPR68 expression is highly upregulated in numerous types of cancer. Emerging evidence has revealed that GPR68 may play crucial roles in tumor biology, including tumorigenesis, tumor growth, and metastasis. This review summarizes current knowledge regarding GPR68-its expression, regulation, signaling pathways, physiological roles, and functions it regulates in human cancers (including prostate, colon and pancreatic cancer, melanoma, medulloblastoma, and myelodysplastic syndrome). The findings provide evidence for GPR68 as a potentially novel therapeutic target but in addition, we note challenges in developing drugs that target GPR68.
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PMID:GPR68: An Emerging Drug Target in Cancer. 3069 14

G protein-coupled receptor 68 (GPR68) is a proton sensor that is activated upon binding to extracellular protons. We have previously found that GPR68 induces a proapoptotic pathway in bone marrow (BM) cells from the patients with myelodysplastic syndromes (MDS) after treated with lenalidomide. However, the function of GPR68 in normal hematopoietic cells remains unclear. With genetic loss of function approach, we found reduced frequency and number of B lymphocytes in the peripheral blood (PB) of whole body Gpr68-/- mice compared to control littermates upon aging. During hematopoietic regeneration, such as in response to fluorouracil (5-FU), we also found reduced frequency and number of B lymphocytes in Gpr68-/- mice compared to wild type mice. Mechanism studies revealed that Gpr68 expression was upregulated in B lymphocytes of BM during aging and in hematopoietic progenitor cells after treatment with 5-FU. In addition, activation of Gpr68 by its activators increased the frequency and number of B lymphocytes. Our studies indicate that Gpr68 expression is upregulated in hematopoietic cells upon aging and during hematopoietic regeneration that ends up with increased number of B lymphocytes.
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PMID:G protein-coupled receptor 68 increases the number of B lymphocytes. 3241 98

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.
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PMID:Cyclosporine enhances the sensitivity to lenalidomide in MDS/AML in vitro. 3243 9

The immunomodulatory drug lenalidomide is used for the treatment of certain hematologic malignancies, including myelodysplastic syndromes (MDS). Lenalidomide interacts with cereblon (CRBN), a component of the CRL4CRBN E3 ubiquitin ligase complex, leading to ubiquitination and subsequent degradation of substrates, such as transcription factor Ikaros (Ikaros family zinc finger 1, IKZF1). With a genome loss of function screen, we recently identified two novel pathways mediated by lenalidomide in MDS. In this review, we summarized the major findings of these two pathways and their clinical implications. Depletion of G protein-coupled receptor 68 (GPR68) or an endogenous calcineurin (CaN) inhibitor, regulator of calcineurin 1 (RCAN1), reversed the inhibitory effect of lenalidomide on MDSL cells, an MDS cell line. Intriguingly, both GPR68 and RCAN1 expression levels were upregulated in MDSL cells after treatment with lenalidomide that was dependent on diminishment of IKZF1, indicating that IKZF1 functioned as a transcription repressor for GPR68 and RCAN1. Mechanistic studies revealed that upregulation or activation of GPR68 induced a Ca2+/calpain pro-apoptotic pathway, while upregulation of RCAN1 inhibited the CaN pro-survival pathway in MDSL cells. Notably, the pharmacological CaN inhibitor, cyclosporine, enhanced the sensitivity to lenalidomide in MDS as well as acute myeloid leukemia (AML). Surprisingly, pretreatment with lenalidomide reversed the immunosuppressive effects of cyclosporine on T lymphocytes. Our studies suggest that lenalidomide mediates degradation of IKZF1, leading to derepression of GPR68 and RCAN1 that activates the Ca2+/calpain pro- apoptotic pathway and inhibits the CaN pro-survival pathway, respectively. Our studies implicate that cyclosporine extends the therapeutic potential of lenalidomide to myeloid malignancies without compromising immune function.
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PMID:Cyclosporine Broadens the Therapeutic Potential of Lenalidomide in Myeloid Malignancies. 3298 63