Project description:We collected three timepoint blood samples from a CLL patient underwent BTK inhibitor treatment. We performed single cell RNA sequencing on these samples to track expression heterogeneity of malignant B-cell populations over time.
Project description:Serial blood draws from a single patient and serial tumor biopsies from the same patient with metastatic Merkel cell polyomavirus Merkel cell carcinoma, who was treated with cellular immunotherapy targeting MCPyV (autologous endogenous T cell therapy) followed by checkpoint inhibitors (anti-PD1 and anti-CTLA4). The patient had a 22 month clinical response followed by late/acquired resistance. We performed scRNAseq using the 10x genomics 3' Chromium expression assay to determine potential mechanisms contributing to immunotherapy response and late resistance
Project description:The functional consequences of many of the genetic changes, or combinations of genetic changes, in chronic lymphocytic leukaemia (CLL) are not known, but it is essential to discover these in order to understand the biology of the disease and the causes of individual variation in response to novel and conventional treatments. In this proof-of-principle study the translational landscape of CLL was determined for the first time by ribosome profiling. Individual variation in response to stimuli from the tumour microenvironment has not been systematically explored previously, but is likely to influence response to treatment and survival.
Project description:High genomic complexity (HGC) is linked to poor prognosis in chronic lymphocytic leukaemia (CLL), but its independent prognostic value remains uncertain amid emerging biomarkers. Therefore we analysed copy number alterations in 495 treatment-naïve patients from three randomized trials (CLL4, ADMIRE, ARCTIC), incorporating IGHV status, telomere length (TL), targeted sequencing, and DNA-methylation subtypes.
Project description:Richter's syndrome (RS) is an aggressive transformation of Chronic Lymphocytic Leukaemia (CLL) frequently due to TP53, CDKN2, MYC or NOTCH1 mutations. whereas a significant proportion displays no specifically acquired driver mutation. We observe constitutive AKT phosphorylation not only in high-risk CLL patients harbouring p53 and NOTCH mutations but also in numerous RS patients. Consistently, genetic over-activation of AKT within the Eµ-TCL1 CLL mouse model results in a high-grade lymphoma phenotype of Richters syndrome. Multiomics assessment of our novel mouse model revealed a S100 defined subcluster of highly proliferative lymphoma cells developing from indolent CLL-like B-cells as a consequence of sudden NOTCH activation being fueled by enhanced NOTCH ligand exposure from T-cells in the microenvironment. Our data link AKT and NOTCH signaling in patient samples, genomic alterations, phosphoproteome and single-cell transcriptome profiles. Collectively, we have identified active AKT as a causative transforming pathway of indolent CLL towards aggressive RS thus providing novel mechanistic insights into the molecular understanding of RS.