Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1073528 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27873617.fastq.gz | Fastqsanger.gz | |||
| SRR27873618.fastq.gz | Fastqsanger.gz |
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Project description:Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [RNA-seq]
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Project description:Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [ATAC-seq]
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Project description:While therapies targeting CD19 by antibodies, CAR-T cells and T cell engagers have improved the response rates in B-cell malignancies; the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19-immunotoxin. Single-cell (sc) RNAseq showed increase in transcriptionally distinct CD19low populations in resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19low resistant cells. ATAC-seq showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B-ALL that relapsed after CD19 CAR-T targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19low resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both BTK and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.
2024-03-06 | GSE255306 | GEO
Project description:While therapies targeting CD19 by antibodies, CAR-T cells and T cell engagers have improved the response rates in B-cell malignancies; the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19-immunotoxin. Single-cell (sc) RNAseq showed increase in transcriptionally distinct CD19low populations in resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19low resistant cells. ATAC-seq showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B-ALL that relapsed after CD19 CAR-T targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19low resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both BTK and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.
2024-03-06 | GSE255305 | GEO
Project description:Chimeric antigen receptor (CAR) T cells targeting CD19 are highly effective against B-lineage malignancies. However, about half of patients either fail to achieve complete remission (in the case of lymphoma) or relapse (in the case of acute lymphoblastic leukemia). CD22 represents an alternative highly B-lineage-restricted target. Although CD22-targeted CAR T cells are clinically active, targeting this antigen has proven difficult relative to CD19, attributable, in part, to lower expression levels. Commonly, patients relapse or progress with reduced CD22 expression compared to pre-treatment, contrasting with the loss of CD19 expression typically observed after CD19-CAR therapy. Prior work demonstrated that an antigen-independent “tonic” signaling CD22-CAR has enhanced clinical efficacy relative to other CD22-CARs tested. However, tonic signaling has been shown to be detrimental to long-term CAR T cell function. Here, we demonstrate a balance between binding affinity and antigen-independent signaling (determined by length of the linker between fragment variable regions) in determining CAR function against CD22. We show that CAR function against both CD22Lo and WT leukemia can be augmented by boosting binding affinity without shortening the linker to induce tonic signaling, establishing rational combinatorial modification of antigen binding domain as an important approach for modulating the function of cellular therapeutics.
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Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is caused by abnormal expansion of immature B cells. Genetic alterations can be identified in most of the BCP-ALL cases, however, some specific lesions including rearrangements of the mixed lineage leukemia (MLL) gene encoding lysine methyltransferase 2A (KMT2A) are associated with particularly poor prognosis. This MLL-rearranged subtype of leukemia poorly responds to conventional treatment and frequently undergoes a lymphoid-to-myeloid lineage switch in response to CD19-directed immunotherapy with consequent loss of B cell-specific targets for immunotherapy. Therefore, there is an urgent need to identify new targets for treatment of relapsed/refractory MLLr-BCP-ALL. Attractive targets may be found in a cell surfaceome, as membrane proteins are often expressed abnormally on cancer cells and are more accessible for therapeutics. Membrane proteins also play key roles in mediating external signaling and interactions with the microenvironment, thus being essential for cancer cell survival. RNA-based data may not always correlate with plasma membrane protein levels. Therefore, we performed the analysis of the BCP-ALL cell surfaceome by biotin labeling of plasma membrane proteins followed by tandem mass spectrometry (LC-MS/MS). This method requires high cell input and therefore was previously applied mainly to cell lines. However, the cell lines often do not fully represent primary samples due to genetic modifications and culture conditions. We have optimized the protocol of plasma membrane protein isolation and LC-MS/MS identification of patient-derived xenografts (PDXs) BCP-ALL cells. We confirmed the LC-MS/MS results by flow cytometry. Additionally, we compared the surfaceomes of PDXs BCP-ALL cells with BCP-ALL cell lines. We profiled six BCP-ALL PDXs and one cell line SEM, all with MLL translocations. In BCP-ALL PDXs we identified 1409 membrane-associated proteins, 945 of which were present in at least 3 samples. Tissue specificity analysis demonstrated that 93 of these proteins are specific for lymphoid cells, including already reported promising immunotherapeutic targets CD19, CD22, CD38, CD70, CD72, CD79A, and CD79B. The expression of selected proteins was confirmed by flow cytometry and compared to the expression on B-ALL cell lines with MLL translocation. Moreover, we identified an additional subset of proteins with potential therapeutic significance, including CD48, IL7R, ITGB7, LAIR1, LILRB1. Importantly, we observed profound differences between surfaceomes of BCP-ALL cell lines and PDX cells.
2025-06-09 | PXD058992 | Pride
Project description:Chimeric antigen receptor (CAR) therapy targeting CD19 yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for over-expressed molecules with potentially tolerable systemic expression. We integrated large transcriptomics and proteomics data sets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34+CD38– hematopoietic cells, T cells or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.
2017-10-24 | PXD007552 | Pride
Project description:Deletion of genes encoding the E26 transformation-specific (ETS) transcription factors, PU.1 and Spi-B, in B cells (CD19-CreDPB mice) leads to acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 weeks. To identify pathways of leukemic transformation, we compared gene expression in leukemia cells from CD19-CreDPB mice (CD19-CreDPB B220- B-ALL) with B cells from Spi-B knockout (Control DB) or B cells from CD19-CreDPB mice (CD19-CreDPB B220+ B cell)
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Project description:GEP on Affymetrix U133+2.0 microarrays was performed on ex vivo CD19+ B lymphocytes or CD19-CD22- fractions from reactive or FL lymph nodes or normal tonsils.
2019-05-27 | GSE107367 | GEO
Project description:CAR T-cell therapy has led to tremendous successes in the treatment of B-cell malignancies. However, 30%-50% of treated patients relapse – often with reduced target antigen expression. We report that anti-CD19 CAR T-cells cause a rapid reduction of CD19 expression within hours in CAR-T exposed CD19+ B-ALL cells. Initially, anti-CD19 CAR T-cells cause CD19 clusters at the T-cell – leukemia cell interface followed by CD19 internalization and decreased CD19 surface expression. Subsequently, CD19 expression is repressed by transcriptional rewiring. Using single-cell RNA-seq and single-cell ATAC-seq we demonstrate that a subset of CD19low cells that are refractory to CAR T-cell killing employ transcriptional programs of physiological B-cell activation and germinal center reaction in order to sustain decreased CD19 expression. Inhibiting B-cell activation programs with the BTK inhibitor ibrutinib increased the cytotoxic efficacy of anti-CD19 CAR T-cells without effecting CAR T-cell viability. These results demonstrate transcriptional plasticity as an underlying mechanism of CAR T-resistance and highlight the importance of combining CAR T-cell therapy with targeted therapies that aim to overcome this plasticity.
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