Genome-wide Methylation Profiling in MBL and from Early to Advanced CLL
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ABSTRACT:
PROVIDER: PRJNA398707 | 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.
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Project description:Here we measured genome-wide DNA methylation in patients with chronic lymphocytic leukemia as it provides an opportunity to capture the emergence of altered methylation landscapes as well as track their dynamics over disease progression including after treatment. Specifically, our cohort includes 21 CLL cases with up to six different time points, 20 precursor states of monoclonal B cell lymphocytes (MBL) and 5 matched samples from MBL and CLL states of the same patients. We find that across all CLL cases, a highly aberrant methylation state was present consistently already at the first time point and maintained with remarkable stability over disease progression. To improve our resolution and address heterogeneity we sequenced the methylome of single cells from CD5 positive and negative naïve and memory B cells as well as unsorted B cells and CLL cells. Methylation levels were highly similar within groups pointing to a rather homogeneous population and contrasted by pronounced differences between naïve and memory B cells that do not distinguish CD5 positive and negative subgroups. Our 20 patients with MBL further confirmed the early emergence of this landscape and surprisingly, the chemotherapy did not have a notable impact on the altered methylome despite a strong depletion of white blood cells.
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Project description:Genome-wide Methylation Profiling in MBL and from Early to Advanced CLL
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Project description:MBL-1 is an RNA-binding protein important for the differentiation and development of many animal tissues. Our aim was to identify the binding targets of the MBL-1 protein in C. elegans. RNA from a CRISPR/CAS9-generated strain expressing a 3xFLAG-tagged MBL-1 protein was immunopreciprecipitated with an anti-FLAG antibody. RNA-seq was then performed to identify binding targets of the RNA-binding protein MBL-1. Experiments were performed at the L4 stage.
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Project description:In the present study, the methylation profiling (MeDIP) was carried out in 14 treatment-naive, early stage (Rai stage 0-2) CLL patients and pooled 19+ normal controls. To find an association of methylation with IGHV mutation status, CLL patients were further segregated into IGHV unmutated (n=9) and IGHV mutated (n=5) subgroups. The methylation signature obtained for CLL versus nornal controls and; unmutated versus mutated CLL was integrated with gene expression profile of these patients and the results were correlated with clinical outcome.
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