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CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [scRNAseq]

ABSTRACT: CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [scRNAseq]

PROVIDER: PRJNA1067675 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27685487.fastq.gz	Fastqsanger.gz
	SRR27685488.fastq.gz	Fastqsanger.gz

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Similar Datasets

CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [scRNAseq]

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

CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [bulkRNAseq]

2024-01-27 | GSE253920 | GEO

CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression

Project description:CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression

| PRJNA1067666 | ENA

CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [bulkRNAseq]

Project description:CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression [bulkRNAseq]

| PRJNA1067673 | ENA

CD38-directed, single-chain T cell-engager targets leukemia stem cells through IFNγ-induced CD38 expression

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-27 | GSE253922 | GEO

CLL: CD38+CD49d+ vs. CD38-CD49d-

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

UBIQUITIN LIGASE STUB1 DESTABILIZES IFNγ-RECEPTOR COMPLEX TO SUPPRESS TUMOR IFNγ SIGNALING

Project description:The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about 36 regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identified STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1K285 and JAK1K249. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This was corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response was increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.

2022-03-07 | PXD030580 | Pride

Analysis of CD38+ and CD38- sub-clones derived from the same CLL patient

Project description:CD38 expression is an important prognostic marker in CLL with high levels of CD38 associated with shorter overall survival. In this study, we used gene expression profiling and protein analysis of highly purified cell-sorted CD38+ and CD38- chronic lymphocytic leukemia cells to elucidate a molecular basis for the association between CD38 expression and inferior clinical outcome. Paired CD38+ and CD38- CLL cells derived from the same patient were shown to be monoclonal by VH gene sequencing but despite this, CD38+ CLL cells possessed a distinct gene expression profile when compared with their CD38- sub-clones. Keywords: Sub-clonal analysis of CLL cells derived from the same leukemia sample

2006-11-23 | GSE6321 | GEO

Single cell RNA-sequencing (scRNA-seq) of the human hematopoietic stem cell compartment (CD34+CD38-CD45RA-)

Project description:To identify a trajectory of human hematopoietic stem cell (HSC) activation we performed scRNAseq of CD34+CD38—CD45RA—cells from G-CSF-mobilized peripheral blood from 3 donors. We show that INKA1 and CDK6/PAK4 expressing single cells segregate across alternative states of quiescence.

2021-03-25 | GSE148884 | GEO

Expression data from native ZAP-70+CD38+ vs. ZAP-70-CD38- CLL cells

Project description:B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course and analysis of ZAP-70 and CD38 expression on B-CLL cells allowed for identification of patients with good (ZAP-70-CD38-), intermediate (discordant expression of ZAP-70 and CD38) and poor (ZAP-70+CD38+) prognosis. In an attempt to identify a molecular basis that may underly this diverse clinical behaviour DNA microarray technology was employed to compare eight ZAP-70+CD38+ with eight ZAP-70-CD38- B-CLL cases. We used microarrays to detail the global programme of gene expression distinguising B-CLL from patient with good (samples 1 to 8) and poor prognosis (sample 9 to 16) and identified distinct classes of up- and down-regulated genes. Keywords: Disease progression

2006-09-22 | GSE4392 | GEO

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