Autoantigen promotes progression to aggressive TCL1 leukemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE45481 | GEO | 2013/05/01
SECONDARY ACCESSION(S): PRJNA194134
REPOSITORIES: GEO
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Project description:Activated BCR signaling in Murine CLL leukemia cells responsive to autoantigen phosphatidylcholine Murine CLL cells obtained from spleen and peritoneum were compared for the genetic signatures associated with autoantigen responsiveness
2013-05-01 | E-GEOD-45481 | biostudies-arrayexpress
Project description:(Auto)antigen engagement by the B-cell receptor (BCR) and possibly the sites where this occurs influence the outcome of chronic lymphocytic leukemia (CLL). To test if selection for autoreactivity leads to increased aggressiveness and if this selection plays out equally in primary and secondary tissues, we used T-cell leukemia (TCL)1 cells reactive with the autoantigen phosphatidylcholine (PtC). After repeated transfers of splenic lymphocytes from a single mouse with oligoclonal PtC-reactive cells, outgrowth of cells expressing a single IGHV-D-J rearrangement and superior PtC-binding and disease virulence occurred. In secondary tissues, increased PtC-binding correlated with enhanced BCR signaling and cell proliferation, whereas reduced signaling and division of cells from the same clone was documented in cells residing in the bone marrow, blood, and peritoneum, even though cells from the last site had highest surface membrane IgM density. Gene-expression analyses revealed reciprocal changes of genes involved in BCR-, CD40-, and PI3K-signaling between splenic and peritoneal cells. Our results suggest autoantigen-stimulated BCR signaling in secondary tissues promotes selection, expansion, and disease progression by activating pro-oncogenic signaling pathways, and that--outside secondary lymphoid tissues--clonal evolution is retarded by diminished BCR-signaling. This transferrable, antigenic-specific murine B-cell clone (TCL1-192) provides a platform to study the types and sites of antigen-BCR interactions and genetic alterations that result and may have relevance to patients.
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Project description:Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Yet, subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter’s transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG using the Illumina 450k methylation arrays. Additionally we analysed the methylation profiles of naive and memory B cell subsets from healthy donors and compared them with those of the CLL cases.
2019-04-04 | E-MTAB-6955 | biostudies-arrayexpress
Project description:B cell chronic lymphocytic leukemia (CLL) is often preceded by a benign monoclonal or oligoclonal CD5+ B cell lymphocytosis. We have generated transgenic mice expressing a catalytically inactive, dominant-negative recombination activating gene 1 (dnRAG1 mice) in the periphery. These animals develop an early-onset indolent CD5+ B cell lymphocytosis, caused in part by a defect in secondary V(D)J rearrangements initiated to alter autoreactive B cell receptor specificity. Hypothesizing that the CD5+ B cells accumulating in dnRAG1 mice represent a CLL precursor, we crossed dnRAG1 mice with CLL-prone Eµ-TCL1 mice to determine whether dnRAG1 expression in Eµ-TCL1 mice accelerates the onset of CLL-like disease. We find that CD5+ B cell expansion and CLL progression occurs more rapidly and uniformly in double-transgenic mice (DTG mice) compared to Eµ-TCL1 mice, but with similar phenotypic and leukemogenic features. To gain insight into genes or pathways responsible for CD5+ B cell accumulation in the transgenic mice, we performed comparative gene expression profiling studies using normal and CD5+ B cells isolated from wild-type and transgenic mice at either 12 weeks of age (pre-leukemia) or at CLL onset in DTG mice (using age-matched wild-type and single-transgenic mice as controls). These analyses confirm the upregulation of tolerogenic genes in CD5+ B cells and reveal a possible role for prolactin signaling in the regulation of receptor editing. This study suggests that a failure to remodel B cell antigen receptor genes in response to autoreactivity may promote the benign accumulation of CD5+ B cells, which may then be subjected to secondary genetic lesions that promote CLL progression.
2013-06-04 | GSE44940 | GEO
Project description:B cell chronic lymphocytic leukemia (CLL) is often preceded by a benign monoclonal or oligoclonal CD5+ B cell lymphocytosis. We have generated transgenic mice expressing a catalytically inactive, dominant-negative recombination activating gene 1 (dnRAG1 mice) in the periphery. These animals develop an early-onset indolent CD5+ B cell lymphocytosis, caused in part by a defect in secondary V(D)J rearrangements initiated to alter autoreactive B cell receptor specificity. Hypothesizing that the CD5+ B cells accumulating in dnRAG1 mice represent a CLL precursor, we crossed dnRAG1 mice with CLL-prone Eµ-TCL1 mice to determine whether dnRAG1 expression in Eµ-TCL1 mice accelerates the onset of CLL-like disease. We find that CD5+ B cell expansion and CLL progression occurs more rapidly and uniformly in double-transgenic mice (DTG mice) compared to Eµ-TCL1 mice, but with similar phenotypic and leukemogenic features. To gain insight into genes or pathways responsible for CD5+ B cell accumulation in the transgenic mice, we performed comparative gene expression profiling studies using normal and CD5+ B cells isolated from wild-type and transgenic mice at either 12 weeks of age (pre-leukemia) or at CLL onset in DTG mice (using age-matched wild-type and single-transgenic mice as controls). These analyses confirm the upregulation of tolerogenic genes in CD5+ B cells and reveal a possible role for prolactin signaling in the regulation of receptor editing. This study suggests that a failure to remodel B cell antigen receptor genes in response to autoreactivity may promote the benign accumulation of CD5+ B cells, which may then be subjected to secondary genetic lesions that promote CLL progression. dnRAG1 mice were bred to Eµ-TCL1 mice to obtain cohorts of wild-type (WT), single-transgenic (dnRAG1 and Eµ-TCL1), and DTG mice. Splenic CD19+B220hiCD5- B cells from WT mice or CD19+CD5+ B cells from transgenic mice were purified using fluorescence activated cell sorting (FACS). Biotin end-labeled cDNA prepared from the sorted cells was hybridized to Mouse Gene 1.0 ST Arrays. These experiments were performed two independent times: once with a cohort of 12-week-old mice, and once with older mice (>34 weeks old) consisting of two ill DTG mice and their age-matched counterparts. At least two biological replicates were used where possible.
2013-06-04 | E-GEOD-44940 | biostudies-arrayexpress
Project description:The B-cell receptor (BCR) signaling is crucial for the pathophysiology of chronic lymphocytic leukemia (CLL). Although the BCR has recently emerged as a new therapeutic target the precise mechanisms by which BCR signaling controls neoplastic B-cell proliferation are still ill characterized. Here, by comparing proliferating vs. non-proliferating cells from aggressive CLL patients, we longitudinally characterized the transcriptional and proteomic response of CLL cells after BCR engagement ex vivo. Of the 5,733 genes and/or proteins which expression was modulated after BCR activation, we identified a CLL proliferative signature including 430 genes and 374 proteins. Mathematical modelling of this signature revealed a nested sub-regulatory network comprising transcription factors activated within hours after cell activation linked to proteins involved in cell proliferation days after stimulation. The mining of this core cellular program sustaining primary human cancer cells proliferation provides an evidence based-resource for innovative therapeutic perspectives.
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Project description:The B-cell receptor (BCR) signaling is crucial for the pathophysiology of chronic lymphocytic leukemia (CLL). Although the BCR has recently emerged as a new therapeutic target the precise mechanisms by which BCR signaling controls neoplastic B-cell proliferation are still ill characterized. Here, by comparing proliferating vs. non-proliferating cells from aggressive CLL patients, we longitudinally characterized the transcriptional and proteomic response of CLL cells after BCR engagement ex vivo. Of the 5,733 genes and/or proteins which expression was modulated after BCR activation, we identified a CLL proliferative signature including 430 genes and 374 proteins. Mathematical modelling of this signature revealed a nested sub-regulatory network comprising transcription factors activated within hours after cell activation linked to proteins involved in cell proliferation days after stimulation. The mining of this core cellular program sustaining primary human cancer cells proliferation provides an evidence based-resource for innovative therapeutic perspectives.
2021-09-08 | PXD013696 | Pride
Project description:we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in a transgenic mouse model of CLL Key words; B-cell antigen receptor (BCR), chronic lymphocytic leukaemia (CLL), T-cell leukemia (TCL)
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Project description:The expression of ZAP-70 in a subset of CLL patients strongly correlates with a more aggressive clinical course, though the exact underlying mechanisms remain elusive. The ability of ZAP-70 to enhance B cell receptor (BCR) signaling, independently of its kinase function, likely contributes. Here we employed RNA-sequencing and proteomic analyses of primary cells and cell lines, differing only in their expression of ZAP-70, to further define how ZAP-70 increases aggressiveness of CLL. We identified that ZAP-70 is required for the constitutive expression of T cell chemokines and the MHC class I molecule CD1c in the absence of an overt BCR signal, both promoting interactions with T cells. In addition, quantitative mass spectrometry of double-cross linked ZAP-70 complexes demonstrated that direct protein-protein interactions between ZAP-70 and cytoskeletal proteins positively regulate cell migration, irrespectively of CCR7 expression. Importantly, these functions of ZAP-70 did not require antigen-stimulation of the BCR. In contrast, we observed that ZAP-70 rapidly forms complexes with ribosomal proteins in BCR-activated cells, while decreasing the expression of ZAP-70 significantly reduced protein biosynthesis, providing evidences that ZAP-70 contributes to translational dysregulation in CLL. In conclusion, ZAP-70 promotes microenvironment-interactions and protein-translation in CLL cells, both likely to improve cellular fitness and to further drive disease progression.
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Project description:Chronic Lymphocytic Leukaemia (CLL) is the most common leukemia in adults in the Western world. B cell receptor (BCR) signalling is known to be crucial for the pathogenesis and maintenance of CLL cells develop from mature CD5+ B cells. BCR signalling is regulated by the inhibitory co-receptor Siglec-G and Siglec-G-deficient mice have an enlarged CD5+ B1a cell population. Here, we determine how Siglec-G expression influences the severity of CLL.
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