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Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [RNA-seq]

ABSTRACT: Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [RNA-seq]

PROVIDER: PRJNA1074409 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27907692_1.fastq.gz	Fastqsanger.gz
	SRR27907692_2.fastq.gz	Fastqsanger.gz
	SRR27907693_1.fastq.gz	Fastqsanger.gz
	SRR27907693_2.fastq.gz	Fastqsanger.gz

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Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [ATAC-seq]

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

Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [RNA-seq]

2024-03-06 | GSE255306 | GEO

Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [ATAC-seq]

Project description:Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency [ATAC-seq]

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Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency.

Project description:While therapies targeting CD19 by antibodies, chimeric antigen receptor T cells (CAR-T), 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 RNA-Seq (scRNA-Seq) showed an increase in transcriptionally distinct CD19lo populations among resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19lo-resistant cells. An assay for transposase-accessible chromatin with sequencing (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 cell acute lymphoblastic leukemia (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. CD19lo resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both Bruton's tyrosine kinase (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.

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Project description:Immunotherapy-resistant acute lymphoblastic leukemia cells exhibit reduced CD19 and CD22 expression and BTK pathway dependency

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CD22 interactome

Project description:CD22 (Siglec-2) is a member of the Siglec family. It is an inhibitory co-receptor of the B-cell-receptor (BCR) and inhibits B–cell activation. Upon BCR stimulation ITIMs in the cytoplasmic tail of CD22 are phosphorylated. This triggers CD22 signalling pathways, which lead to a decreased calcium mobilization in the B cell and thus an inhibition of BCR signalling. Although some CD22 binding partners, such as the phosphatase SHP-1, have already been identified, we deciphered the CD22 interactome in more detail, to gain a deeper understanding of CD22 molecular mechanisms and signalling events after BCR activation. Stable isotope labelling of amino acids in cell culture (SILAC) in combination with mass spectrometry analysis enabled the identification of specific CD22 interaction partners in a quantitative proteomics approach. Hereby, several new CD22 associated proteins were identified that have not been linked to CD22 yet. One of those interacting proteins is cullin 3, an E3 ubiquitin ligase. It was revealed that cullin 3 is important for clathrin-dependent CD22 internalization after BCR stimulation and CD22 surface expression. Further analysis of B-cell specific cullin 3 deficient mice showed an important role of cullin 3 in B cell development. These mice have strongly reduced numbers of mature B cells in the periphery, which are characterized by increased CD22 expression and additionally by pre-activated and apoptotic phenotypes.

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CD22 modulation regulates neuroinflammation in microglia

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Role of IL-2 inducible T cell kinase (ITK) and Bruton's tyrosine kinase (BTK) in mast cell response to lipopolysaccharide (LPS)

Project description:Mast cells are indispensable for LPS-induced septic hypothermia, in which TNF-Î± plays an essential role to initiate sepsis. Tec family non-receptor tyrosine kinases ITK and BTK regulate mast cell-derived TNF-Î± in response to allergic antigen, but their role in LPS-induced TNF-Î± production by mast cells and related pathology is unclear. We sought to investigate the role(s) of ITK and BTK in mast cell response in septic condition. We found that the absence of ITK and BTK leads to enhanced TNF-Î± production by bone marrow-derived mast cells (BMMC). Itk-/-Btk-/- mast cells exhibit hyperactive preformed and LPS-induced TNF-Î± production, along with enhanced expression of other related genes such as NF-ÎºB targeted genes, compared to WT cells. Bone marrow cells from 8-week old WT, Itk-/-, Btk-/- and Itk-/-Btk-/- (double knockout: DKO) C57Bl/6 mice were cultured in murine Interleukin-3/Stem cell factor (IL-3/SCF) supplemented medium for 5 weeks to derive mast cells. WT, Itk-/-, Btk-/- and DKO bone marrow-derived mast cells (BMMC) were factor starved in medium without IL-3/SCF for 12 hours, followed by treatment with PBS (control) or 100 ng/ml LPS for 1 hour. Triplicates of each group were subjected to mouse whole genome genechip microarray analysis. Replicates were randomized on different chips to avoid systematic error.

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