Gene expression changes between lenalidomide (LEN)-sensitive and LEN-resistant human multiple myeloma (MM) cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE222411 | GEO | 2023/07/01
REPOSITORIES: GEO
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Project description: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.
2016-06-08 | GSE82235 | GEO
Project description:To identify epigenetically silenced genes in multiple myeloma (MM) cell lines and to determine the effects of 5-aza-2-deoxycytidine and trichostatin A on gene expression. We treated 3 multiple myeloma cell lines (MM1, NCI-H929, U266) with 5-aza-2-deoxycytidine and/or trichostatin A.
2008-02-01 | E-MEXP-1269 | biostudies-arrayexpress
Project description:We have measured the proteomic changes on ANBL6, IH1, INA6, U266, KJON, OH2, VOLIN, LR5, KARPAS, RAMOS cell lines and used it to build a super SILAC library in order to quantify proteomic changes from MGUG to MM stages of Myeloma with Elite orbitrap mass spetrometer.
2024-06-07 | PXD006458 | Pride
Project description:Even after the development of tyrosine kinase inhibitors (TKIs), the long-term prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is still unsatisfactory, which is thought to be associated with the high incidence of genetic alterations of Ikaros family zinc finger 1 (IKZF1). Lenalidomide (LEN), a representative of immunomodulatory drugs (IMiDs), has been effectively used for the treatment of relapsed/refractory multiple myeloma (MM), and its cytotoxic effect was recently shown to be mediated, at least in part, by marked down-regulation of IKZFs 1 and 3 expression through the interaction with the receptor cereblon (CRBN) forming a part of the Cullin-RING E3 ubiquitin ligase. In the present study, we examined the effects of LEN on ALL cells with a variety of genetic alterations and found that Ph+ALL cells expressing a dominant-negative IKZF1 isoform Ik6 which lacks the CRBN binding site were specifically sensitive to LEN where accumulation of Ik6 with disappearance of functional IKZF1 isoforms and the abrupt fall from very high levels of IKZF3 expression were documented. To examine the effect of lenalidomide and/or imatinib treatment on Ph-positive ALL cells from the viewpoint of gene expression, we performed micro array analysis. Of importance, the induction of apoptosis of Ph+ALL cells, even with the T315I mutation of BCR-ABL, was enhanced when they were treated with TKI in the presence of LEN. This synergism between LEN and TKIs was demonstrated in the xenograft mice model. IMiDs, now called as CRBN modulators, should be an attractive approach for potentiating responsiveness of Ph+ALL cells to TKIs, and this drug repositioning certainly facilitates their long-term survival if the effective combination regimen is warranted.
2021-06-16 | GSE155597 | GEO
Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included two isogenic MM1.S cell lines, which differ in the sensibiligy to lenalidomide. We included MM1.S and MM1.S res, which were sensitive and resistant to lenalidomide, respectively.
2011-09-30 | E-GEOD-31451 | biostudies-arrayexpress
Project description:The RNA-seq data presented in this study include libraries from bone marrow plasma cells (BMPC), primary myeloma cells (BMMCs) from 7 patients, and myeloma cell line MM1.S and KMS12
2018-12-28 | GSE76425 | GEO
Project description:Multiple myeloma (MM)-induced osteoclast (OC) formation occurs in close contact with MM cell infiltration into the bone marrow (BM) due to the imbalance of the receptor activator of NF-kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio in favor of RANKL in the micorenvironment. Soluble factors including CCL3/MIP-1?, IL7 and IL-3 also contribute to the increased OC formation in MM.The immunomodulatory drugs (IMiD®s) directly inhibit OCs, however their effect on the mechanisms involved in MM-induced OC formation are not known and have been investigated in this study. We found that both Lenalidomide (LEN) and Pomalidomide (POM), at concentration ranging reached in vivo, significantly blunted RANKL up-regulation normalizing the RANKL/OPG ratio in human BM osteoprogenitor cells (PreOBs) co-cultured with MM cells and inhibited CCL3/MIP-1? production by MM cells. The reduction of CD49d expression on MM cells, a molecule critically involved in RANKL up-regulation in the micorenvironment, accompanied this effect. Consistently the pro-osteoclastogenic property of the conditioned medium of MM cells co-cultured with PreOBs was reduced in the presence of both IMiD®s. By microarray analysis we further investigated the effect of POM and LEN on the transcriptional profile of both MM cells and PreOBs. We found a significant down-regulation in MM cells, in addition to CD49d, of genes belonging to the adhesion molecules family such as ITGA8 and ICAM2 (CD102) induced by both IMiD®s compounds. In conclusion our data suggest that POM and LEN inhibits MM-induced OC formation through the inhibition of RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells. This series of microarray experiments contains the gene expression profiles of JJN3 cell line cultured in presence of POM (100 µM), LEN (100 µM) or vehicle in triplicate flasks for 24 hours, respectively. Preparation of biotin-labeled cRNA, hybridization to GeneChip® Human Genome U133 Plus 2.0 Arrays (Affymetrix Inc., Santa Clara, CA, USA) and scanning of the chips (7G Scanner, Affymetrix Inc.) were carried out according to manufacturer's protocols. Expression values were extracted from cell intensity files, using GeneAnnot custom chip definition files. The CDF Packages for R/Bioconductor (http://www.bioconductor.org/) version 2.2.0 was based on GeneAnnot annotation Version 2.0 and publicly available at http://www.xlab.unimo.it/GA_CDF/. The data were normalized using Robust Multi-array Average procedure.
2013-04-13 | E-GEOD-37302 | biostudies-arrayexpress
Project description:Here we report the use of high-throughput sequencing technologies (RNA-seq, ATAC-seq, ChIP-seq) to identify the molecular programme of the transcirption factor c-MAF (MAF) in parental (MM1.S, JJN3, H929), MAF-depleted (MM1S, JJN3) and MAF-overexpressing (MM1S, U266) multiple myeloma (MM) cells . We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) against MAF in naive MM cells , and against MAF, H3K27ac and H3K4me1 in MAF-overexpressing cells. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed on MAF-overexpressing U266 myeloma cells. In addition, we identifed the transcriptome of MAF-depleted myeloma cells 3 days after lentiviral transduction with MAF-targeting shRNA and scbl control. Our integrated -omics approach provides a comprehensive characterization of the role and function of MAF in myeloma cells and provides novel insights towards the discovery and design of molecular targets for precision therapy against MAF-overexpressing MM.
2023-08-01 | GSE210858 | GEO
Project description:Interstitial deletion of the long arm of chromosome 5 (del(5q)) is the commonest structural genomic variant in myelodysplastic syndromes (MDS). Lenalidomide (LEN) is the treatment of choice for patients with del(5q) MDS, but half of the responding patients become resistant within two years. TP53 mutations are detected in ~20% of patients who become resistant to LEN. Our data show that patients who become resistant to LEN harbor either TP53 or RUNX1 mutations or loss of RUNX1 expression. Here we show that LEN-induced degradation of IKZF1 permits a RUNX1/GATA2 complex to drive megakaryocytic differentiation and consequent del(5q) MDS progenitor cell death via CRBN-mediated CSNK1A1 degradation. Overexpression of GATA2 is able to restore LEN sensitivity in the context of RUNX1 or TP53 mutations by enhancing LEN-induced megakaryocytic differentiation. Screening for TP53 and RUNX1 mutations or downregulation should identify patients resistant to LEN, and strategies to activate GATA2 may resensitize del(5q) MDS cells to LEN
| EGAS00001004113 | EGA
Project description:In the field of MDS and on bone marrow mononuclear cells , we search for a signature which predict the response to Lenalidomide treatment. This transcriptome study appended to the GFM-LEN-EPO-2008 clinical trial reports a predictive signature of response to lenalidomide and a unique immune response signature after treatment.
2017-08-24 | GSE102976 | GEO