Effect of Lenalidomide on human macrophages.
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ABSTRACT:
PROVIDER: PRJNA694117 | ENA |
REPOSITORIES: ENA
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Project description:Lenalidomide, an IMiD® immunomodulatory agent used for the treatment of multiple myeloma (MM),is believed to target the stromal support, but its precise mechanism on the phenotype or the effector functions of macrophages is still unclear. To investigate the effect of lenalidomide on macrophages, M-CSF generated macrophages were treated with Lenalidomide and analyzed by RNA-seq.
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Project description:Immunomodulatory drugs (IMiDs), such as lenalidomide provide a tool to enhance both direct anti-tumor and graft-versus-tumor effects after allogeneic haematopoietic stem-cell transplantation (AHCT). However, early clinical experience with IMiDs after AHCT using adult peripheral blood (APB) as a stem cell source has been limited by induction of graft-versus-host disease. Characterization of the mechanisms by which IMIDs can modulate alloresponses of T-cells from different cell sources could facilitate more effective use of these drugs in the setting of AHCT. In this study we have used in vitro modelling to identify changes in alloresponses of APB and umbilical cord blood (UCB) T-cells after exposure to the widely used IMiD lenalidomide. We demonstrate that lenalidomide increases net alloproliferation of APB T-cells by selectively enhancing allospecific proliferation of CD8+ T-cells. These CD8+ T-cells have enhanced effector memory differentiation, are enriched for polyfunctional effectors, and have a distinct gene expression profile with altered expression of key immunoregulatory genes. In contrast, although lenalidomide treatment of UCB T-cells results in a similar increase in alloreactive effector CD8+ T-cells, it also reduces allospecific proliferation of CD4+ T-cells and selectively expands frequencies of CD4+ regulatory T-cells, resulting in a net reduction in UCB T-cell alloproliferation. Our findings show that lenalidomide has a qualitatively different impact on alloresponses of T-cells from different cell sources, with a potentially tolerogenic effect on UCB T-cells. These findings have important implications for the future use of IMiDs in the setting of AHCT.
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Project description:Lenalidomide, an analogue of thalidomide, is immuno-modulatory drug and has been used for many types of cancer therapy. Recently, it has been reported that lenalidomide can enhance the function of NK cell during IL-2 response. However, molecular mechanism of action of lenalidomide in NK cells is unclear still. To investigate the modification by lenalidomide on NK cells, we conducted the analysis of gene expression on NK cells.
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Project description:To clarify the machinery how lenalidomide inhibit proplatelet formation of megakaryocytes, we performed transcriptome analysis of megakaryocytes derived from human hematopoietic stem/progenitor cells in the liquid culture system with or without lenalidomide. Differentially expressed genes were comprehensively evaluated by gene set enrichment analysis. Untreated megakaryocytes showed the estradiol-responded gene expression signatures, whereas the lenalidomide-treated megakaryocytes did not. Furthermore, we performed a rescue strategy with exogenous estradiol, confirming that lenalidomide-induced inhibition of proplatelet formation should be due to the deficiency of endogenous estradiol action in megakaryocytes.
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Project description:Peripheral blood was collected into PAXgene tubes from 7 patients with follicular lymphoma, in a phase 2 clinical trial of lenalidomide plus rituximab as initial therapy for advanced-stage indolent non-Hodgkin's lymphoma. Blood was collected at baseline and on Day 15 of the second 28-day cycle, for determination of the gene expression profile after globin mRNA reduction. The effect of treatment on gene expression profiles was largely based on the paired t test, using the Significance Analysis of Microarrays method.
2014-02-06 | E-GEOD-54740 | biostudies-arrayexpress
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 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.
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