Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early stage chronic lymphocytic leukemia
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PROVIDER: PRJNA517514 | ENA |
REPOSITORIES: ENA
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Project description:Several studies have demonstrated an impaired function of the microenvironment in chronic lymphocytic leukemia (CLL), contributing to immune evasion of tumor cells and disease progression. However, in CLL-like monoclonal B cell lymphocytosis (MBL) studies are scarce. Herein, a comprehensive characterization of the microenvironment in 59 MBL, 56 early stage CLL and 31 healthy controls was conducted. Gene expression arrays and qRT-PCR were performed on RNA from CD4+ peripheral blood cells; serum cytokines were measured by immunoassays and proteomic studies; and flow cytometry was applied to evaluate peripheral blood cytotoxic, Th1, exhausted and effector CD4+ T cells, besides monocytic CD14, CD4 and HLA-DR expression. MBL and early stage CLL showed a similar upregulation of cytotoxic and Th1-related genes, expanded perforin+ and CXCR3+ CD4+ T cells as well as PD1+ CD4+ T cells compared to controls. However, a strong inflammatory response was only identified in MBL: enhanced phagocytosis, pattern recognition receptors, IL8, HMGB1, TREM1 and acute response signaling pathways, along with increased levels of proinflammatory cytokines (remarkably IL8, IFN? and TNF?). Of note, this inflammatory drive was decreased in early stage CLL: diminished proinflammatory cytokines including IFN?, decreased IL8 signaling pathway and lower monocytic HLA-DR expression compared to MBL. Besides, this inflammation was especially reduced in IGHV mutated CLL, involving a decrease of the proinflammatory HMGB1 signaling pathway. These novel findings reveal a different pathophysiology between MBL and CLL, paving the way for the development of pre-emptive immunotherapies with optimal benefits at MBL and early stage CLL, before intense immune exhaustion.
2020-03-29 | GSE125791 | GEO
Project description:Prospective series of 136 clinical monoclonal B lymphocytosis (cMBL) and 216 chronic lymphocytic leukemia (CLL) Rai 0 patients, were investigated in this study. While the distribution of CD38 and ZAP-70 positivity was similar, IGHV-mutated cases were more frequent among cMBL (P = 0.005). A Cox multivariate analysis on the whole patient cohort showed that cMBL condition was predictive of longer PFS, while CD38 expression and IGHV-unmutated status and CD38 expression correlated significantly with a shorter PFS in cMBL and Rai0-CLL, respectively. Trisomy 12, 11q- and 17p- abnormalities were scanty and of no predictive value in both conditions. Notably, gene and miRNA expression profiling showed no significant differences between cMBL and Rai0-CLL. Furthermore, similar gene and miRNA expression signatures were found in cMBL and Rai0-CLL according to the IGHV gene mutational status: that is, unmutated cases had different signatures from mutated cases, irrespectively of the cMBL or CLL condition. Overall, our study based on a prospective series of patients indicates that no major biological differences exist in cMBL compared to Rai0-CLL, suggesting that this two entities mainly differ for the initial size of the monoclonal cell population which may reflect in the longer time for clonal expansion. This series of microarray experiments contains the gene expression profiles of purified B-cell chronic lymphocytic leukemia (B-CLL) cells obtained from 160 patients (Binet stage A) including 45 cMBL and 115 Rai0-CLL. Peripheral blood mononuclear cells from CLL patients were isolated by Ficoll-Hypaque (Seromed, Biochrom KG, Berlin, Germany) density-gradient centrifugation. For gene and miRNA expression profiling experiments CLL cells were enriched by negative selection with the EasySep-Human B cell enrichment kit without CD43 depletion (Stem Cell Technologies) using the fully automated protocol of immunomagnetic cell separation with RoboSepTM (Stem Cell Technologies).
2013-08-30 | E-GEOD-40570 | biostudies-arrayexpress
Project description:Prospective series of 136 clinical monoclonal B lymphocytosis (cMBL) and 216 chronic lymphocytic leukemia (CLL) Rai 0 patients, were investigated in this study. While the distribution of CD38 and ZAP-70 positivity was similar, IGHV-mutated cases were more frequent among cMBL (P = 0.005). A Cox multivariate analysis on the whole patient cohort showed that cMBL condition was predictive of longer PFS, while CD38 expression and IGHV-unmutated status and CD38 expression correlated significantly with a shorter PFS in cMBL and Rai0-CLL, respectively. Trisomy 12, 11q- and 17p- abnormalities were scanty and of no predictive value in both conditions. Notably, gene and miRNA expression profiling showed no significant differences between cMBL and Rai0-CLL. Furthermore, similar gene and miRNA expression signatures were found in cMBL and Rai0-CLL according to the IGHV gene mutational status: that is, unmutated cases had different signatures from mutated cases, irrespectively of the cMBL or CLL condition. Overall, our study based on a prospective series of patients indicates that no major biological differences exist in cMBL compared to Rai0-CLL, suggesting that this two entities mainly differ for the initial size of the monoclonal cell population which may reflect in the longer time for clonal expansion.
2013-08-30 | GSE40570 | GEO
Project description:Prospective series of 136 clinical monoclonal B lymphocytosis (cMBL) and 216 chronic lymphocytic leukemia (CLL) Rai 0 patients, were investigated in this study. While the distribution of CD38 and ZAP-70 positivity was similar, IGHV-mutated cases were more frequent among cMBL (P = 0.005). A Cox multivariate analysis on the whole patient cohort showed that cMBL condition was predictive of longer PFS, while CD38 expression and IGHV-unmutated status and CD38 expression correlated significantly with a shorter PFS in cMBL and Rai0-CLL, respectively. Trisomy 12, 11q- and 17p- abnormalities were scanty and of no predictive value in both conditions. Notably, gene and miRNA expression profiling showed no significant differences between cMBL and Rai0-CLL. Furthermore, similar gene and miRNA expression signatures were found in cMBL and Rai0-CLL according to the IGHV gene mutational status: that is, unmutated cases had different signatures from mutated cases, irrespectively of the cMBL or CLL condition. Overall, our study based on a prospective series of patients indicates that no major biological differences exist in cMBL compared to Rai0-CLL, suggesting that this two entities mainly differ for the initial size of the monoclonal cell population which may reflect in the longer time for clonal expansion.
2013-08-30 | GSE40533 | GEO
Project description:Unveiling key players in the Chronic Lymphocytic Leukemia (CLL)-microenvironment interplay
| PRJNA488214 | ENA
Project description:Chronic lymphocytic leukemia (CLL) is preceded by monoclonal B-cell lymphocytosis (MBL), a CLL precursor state with a prevalence of up to 12% in aged individuals. However, the duration of MBL and the mechanisms of its evolution to CLL remain largely unknown. In this study, we sequenced the B-cell receptor immunoglobulin heavy chain (BcR IGH) gene repertoire of 124 CLL patients and 118 matched controls in blood samples taken up to 22 years prior to diagnosis. Significant skewing in the BcR IGH gene repertoire was detected in the majority of patients, even before the occurrence of lymphocytosis and irrespective of the clonotypic IGH variable gene somatic hypermutation status. Furthermore, in 14 CLL patients we identified dominant clonotypes belonging to major stereotyped subsets associated with poor prognosis up to 16 years before diagnosis. In 22 patients with longitudinal samples, the skewing of the BcR IGH gene repertoire increased significantly over time to diagnosis or remained stable at high levels. For 14/16 patients with available samples at diagnosis, the CLL clonotype was already present in the pre-diagnostic samples. Overall, our data indicate that the pre-clinical phase of CLL could be longer than previously thought, even in adverse-prognostic cases.
2022-06-01 | GSE178208 | GEO
Project description:Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1+ CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.
2021-01-21 | GSE147046 | GEO
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. Experiment Overall Design: These experiments compared the gene expression profile of CD38+ and CD38- sub-clones derived from 6 individual CLL patients.
2007-11-11 | E-GEOD-6321 | biostudies-arrayexpress
Project description:Prospective series of 136 clinical monoclonal B lymphocytosis (cMBL) and 216 chronic lymphocytic leukemia (CLL) Rai 0 patients, were investigated in this study. While the distribution of CD38 and ZAP-70 positivity was similar, IGHV-mutated cases were more frequent among cMBL (P = 0.005). A Cox multivariate analysis on the whole patient cohort showed that cMBL condition was predictive of longer PFS, while CD38 expression and IGHV-unmutated status and CD38 expression correlated significantly with a shorter PFS in cMBL and Rai0-CLL, respectively. Trisomy 12, 11q- and 17p- abnormalities were scanty and of no predictive value in both conditions. Notably, gene and miRNA expression profiling showed no significant differences between cMBL and Rai0-CLL. Furthermore, similar gene and miRNA expression signatures were found in cMBL and Rai0-CLL according to the IGHV gene mutational status: that is, unmutated cases had different signatures from mutated cases, irrespectively of the cMBL or CLL condition. Overall, our study based on a prospective series of patients indicates that no major biological differences exist in cMBL compared to Rai0-CLL, suggesting that this two entities mainly differ for the initial size of the monoclonal cell population which may reflect in the longer time for clonal expansion. This series of microarray experiments contains the microRNA profiles of purified B-cell chronic lymphocytic leukemia (B-CLL) cells obtained from 150 patients (Binet stage A) including 39 cMBL and 111 Rai0-CLL. Peripheral blood mononuclear cells from CLL patients were isolated by Ficoll-Hypaque (Seromed, Biochrom KG, Berlin, Germany) density-gradient centrifugation. For gene and miRNA expression profiling experiments CLL cells were enriched by negative selection with the EasySep-Human B cell enrichment kit without CD43 depletion (Stem Cell Technologies) using the fully automated protocol of immunomagnetic cell separation with RoboSepTM (Stem Cell Technologies). The proportion of CD5/CD19/CD23 triple positive B cells in the suspension was determined by direct immunofluorescence with antibodies for CD19 FITC, CD23 PE and CD5 PC5. 500 nanograms of total RNA was processed in accordance with the manufacturer's protocols (Agilent Technologies) to generate Cy3-labelled RNA, which were purified on chromatography columns (Micro Biospin 6, Bio-Rad, Hercules, CA) and then hybridized on an Agilent microarray (G4470B) at 55C for 17 hr in a rotating oven. Images at 5 um resolution were generated using an Agilent scanner G2505B. The Feature Extraction 10.7.3.1 software (Agilent Technologies) was used to obtain the microarray raw-data. The raw gTotalGeneSignal has been recalculated using the procedures described in Agilent Feature Extraction Software version 10.1 manual. Non-human probes, miRNAs flagged as 'absent' (i.e. expressed below background levels) throughout the whole dataset and miRNAs expired according to Sanger miRBase Release 15 (April 2010) were discarded, and a quantile normalization was applied on raw data using the aroma.light package for Bioconducor. The data were then converted to obtain positive values throughout the dataset, at a minimum value of 1, and log2 transformed.
2013-08-30 | E-GEOD-40533 | 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