Functional multi-omics reveals genetic and pharmacologic regulation of surface CD38 in multiple myeloma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA751385 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15319363.fastq.gz | Fastqsanger.gz | |||
| SRR15319364.fastq.gz | Fastqsanger.gz | |||
| SRR15319365.fastq.gz | Fastqsanger.gz | |||
| SRR15319366.fastq.gz | Fastqsanger.gz | |||
| SRR15319367.fastq.gz | Fastqsanger.gz |
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Project description:The goals of this study are to use multi-omics to design strategies to enhance efficacy of CD38-targeting immunotherapies in myeloma. We compared RNA-seq to cell surface proteomics after genetic and chemical manipulation of CD38 levels in myeloma cell lines.
2021-08-02 | GSE181277 | GEO
Project description:CD38 is a surface ectoenzyme expressed at high levels on myeloma plasma cells and is the target for the monoclonal antibodies (mAbs) daratumumab and isatuximab. CD38 density on tumor cells is an important determinant of mAb efficacy while CD38 is lost after mAb treatment. Several small molecules have been found to increase tumor surface CD38, with the goal of boosting mAb efficacy in a co-treatment strategy. Here we sought to extend our currently limited insight into CD38 surface expression by using a multi-omics approach. Genome-wide CRISPR-interference screens integrated with patient-centered epigenetic analysis confirmed known regulators of CD38, such as RARA, while revealing XBP1 and SPI1 as other key transcription factors governing surface CD38 levels. CD38 knockdown followed by cell surface proteomics demonstrated no significant remodeling of the myeloma “surfaceome” after genetically-induced loss of this antigen. Integrated transcriptome and surface proteome data confirmed high specificity of all-trans retinoic acid in upregulating CD38 in contrast to broader effects of azacytidine and panobinostat. Finally, unbiased phosphoproteomics identified inhibition of MAP kinase pathway signaling in tumor cells after daratumumab treatment. Our work provides a resource to design strategies to enhance efficacy of CD38-targeting immunotherapies in myeloma.
2021-07-29 | PXD027594 | Pride
Project description:Multiple myeloma (MM), the second most common hematological cancer in the United States, is characterized by the proliferation of malignant clonal plasma cells primarily within the bone marrow. The multifunctional cell surface glycoprotein CD38 is expressed in majority of MM cells, making it a key biomarker. Since the FDA approval of daratumumab in 2015, CD38-targeted immunotherapies have significantly advanced the treatment of MM; albeit nonuniform patient response and relapse. The role of CD38 in the complex bone microenvironment remains under investigation. This study examined the effect of CD38 on tumor cells by evaluating a CD38 knock-out (KO) clone of a human MM cell line xenografted into immunodeficient mice. CRISPR/Cas9 gene editing was used to KO CD38 expression in the wild-type (WT) MM.1S human MM cell line (MM.1S-CBR-GFP), confirmed with RNA sequencing and flow cytometry. After tumor implantation in mice, bioluminescence imaging (BLI) was employed to track tumor cells. Small animal Positron Emission Tomography (PET) was performed with the metabolic tracer, fluorodeoxyglucose ([18F]-FDG), and CD38-targeted [89Zr]-Daratumumab, respectively. Post-PET tissue biodistribution and leg bone autoradiography was performed to evaluate tracer distribution. Computed Tomography (CT), dual-energy X-ray (DEXA), and immunohistochemistry were used to evaluate changes in bone mineral density and osteolytic disease. Differences in blood composition, cytokine production, and RNA sequencing between WT and KO mice were analyzed for characterizing the new CD38 KO phenotype. BLI showed significantly increased tumor burden in the CD38 KO MM models compared to WT mice after implantation: 1-week (P=0.0011), 2-weeks (P=0.0066), 3-weeks (P=0.0046), and 4 weeks (P<0.0001). CT and DEXA imaging revealed that the KO mice had significantly decreased bone density, and similarly, planar X-ray imaging indicated severe myeloma bone disease characterized by cortical and trabecular osteolytic lesions in the femur and tibia. Bone histology further confirmed the KO tumor more aggressively invading the bone and muscle tissue. [89Zr]-Daratumumab accumulated in the spine, femur, and tibia in WT MM mice, with minimal bone uptake in the CD38 KO MM mice. [18F]-FDG PET revealed an increased metabolic activity of CD38 KO MM, with an aggressive kinetic uptake of the tracer (P < 0.001). Bilateral kidney metastases were observed in nearly all CD38 KO MM mice, while remaining undetected in WT mice. Blood analysis indicated elevated markers of disease progression and renal dysfunction, with reduced leukocyte and thrombocyte production in the CD38 KO MM xenografts. Cytokine profiling revealed altered levels of pro-inflammatory cytokines, including IL-13, IL-6, RANKL, and VEGF-α in the bone microenvironment of MM with depleted CD38. RNA sequencing showed significant transcriptional changes in CD38 KO cells, suggesting that the observed enhanced aggressiveness is predominantly fueled by the activation of key pathways that promote accelerated cell proliferation, pathways that enhance osteoclast activity, and pathways that enhance metastatic potential.
2025-10-01 | GSE287775 | GEO
Project description:The myeloma cell surface proteome (“surfaceome”) not only determines tumor interaction with the microenvironment but serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to first define surface markers most-enriched on myeloma when compared to B-cell malignancy models, revealing unexpected biological signatures unique to malignant plasma cells. We next integrate our proteomic dataset with existing transcriptome databases, nominating CCR10 and TXNDC11 as possible monotherapeutic targets and CD48 as a promising co-target for increasing avidity of BCMA-directed cellular therapies. We further identify potential biomarkers of resistance to proteasome inhibitors and lenalidomide including changes in CD53, EVI2B, CD10, and CD33. Comparison of short-term treatment with chronic resistance delineates large differences in surface proteome profile under each type of drug exposure. Finally, we develop a miniaturized version of the surface proteomics protocol and present the first surface proteomic profile of a primary MM patient plasma cell sample. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma.
2022-05-27 | PXD022553 | Pride
Project description:Ablation of CD38 on Multiple Myeloma Cells Leads to an Aggressive Phenotype
| PRJNA1214676 | ENA
Project description:The myeloma cell surface proteome (“surfaceome”) not only determines tumor interaction with the microenvironment but serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to first define surface markers most-enriched on myeloma when compared to B-cell malignancy models, revealing unexpected biological signatures unique to malignant plasma cells. We next integrate our proteomic dataset with existing transcriptome databases, nominating CCR10 and TXNDC11 as possible monotherapeutic targets and CD48 as a promising co-target for increasing avidity of BCMA-directed cellular therapies. We further identify potential biomarkers of resistance to proteasome inhibitors and lenalidomide including changes in CD53, EVI2B, CD10, and CD33. Comparison of short-term treatment with chronic resistance delineates large differences in surface proteome profile under each type of drug exposure. Finally, we develop a miniaturized version of the surface proteomics protocol and present the first surface proteomic profile of a primary plasma cell sample. Our dataset provides a unique resource to advance the biological, therapeutic, and diagnostic understanding of myeloma.
2021-12-10 | GSE160572 | GEO
Project description:CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38+CD49d+ vs. CD38-CD49d- CLL cells, we demonstrated overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also upregulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38+CD49d+ but not CD38-CD49d- cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68+ macrophage infiltration was particularly high in BMB from CD38+CD49d+ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express VCAM-1, the CD49d ligand, likely through TNFα over-production. These effects were apparent in BMB from CD38+CD49d+CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1+ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1-transfectants increased viability of CD38+CD49d+ CLL cells. Altogether, CD38 and CD49d can be thought of as a part of a consecutive chain of events ultimately leading to improved survival of CLL cells.
2009-03-03 | GSE14560 | GEO
Project description:Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that IFNγ reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFNγ-induced CD38 upregulation depends on IRF-1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T cell engager (BN-CD38) designed to promote an effective immunological synapse between both CD8 and CD4 T cells and CD38pos AML cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts leading to T cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFNγ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, while BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multi-lineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.
2024-01-27 | GSE253921 | GEO
Project description:Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that IFNγ reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFNγ-induced CD38 upregulation depends on IRF-1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T cell engager (BN-CD38) designed to promote an effective immunological synapse between both CD8 and CD4 T cells and CD38pos AML cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts leading to T cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFNγ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, while BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multi-lineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.
2024-01-27 | GSE253920 | GEO
Project description:Objectives: In gout, flares of severely painful inflammatory arthritis intersect with metabolism, circadian rhythm, and macrophage activation. NAD+ is a necessary cofactor and key metabolite in cellular bioenergy homeostasis, and NAD+ suppresses the NLRP3 inflammasome and inflammation. However, cellular NAD+ declines in inflammatory states, associated with increased activity of the leukocyte-expressed NADase CD38. Gouty arthritis is principally prevented and treated with nonselective and frequently toxic drugs (colchicine, NSAIDs, corticosteroids). Hence, we tested the potential role of therapeutically targeting CD38 and NAD+ in gout. Methods: We studied cultured mouse wild type and CD38 knockout (KO) murine bone marrow derived macrophages (BMDMs) stimulated by monosodium urate (MSU) crystals, and the air pouch gout synovitis model. Results: MSU crystals induced CD38 in BMDMs in vitro, associated with NAD+ depletion, and IL-1b and CXCL1 release, effects reversed by pharmacologic CD38 inhibitors (apigenin, 78c). Mouse air pouch inflammatory responses to MSU crystals were blunted by CD38 KO and apigenin. Pharmacologic CD38 inhibition suppressed MSU crystal-induced NLRP3 inflammasome activation and increased anti-inflammatory SIRT3-SOD2 in macrophages. BMDM RNA-seq analysis of 176 differentially expressed genes (DEGs) revealed CD38 control of multiple MSU crystal-modulated inflammation pathways. The top DEGs included the circadian rhythm modulator GRP176, and the metalloreductase STEAP4 that mediates iron homeostasis, and promotes oxidative stress and NF-kB activation when it is overexpressed. Conclusion: CD38 and NAD+ depletion are druggable targets controlling the MSU crystal- induced inflammation program. Targeting CD38 and NAD+ are potentially novel selective molecular approaches to limit gouty arthritis.
2024-05-08 | GSE214587 | GEO