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: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:The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.
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. Keywords: Sub-clonal analysis of CLL cells derived from the same leukemia sample
Project description:Transcriptional profiling revealed that murine VH11 and non-VH11 CLL differed in the upregulation of specific pathways implicated in cell signaling and metabolism. We identified a gene expression signature (including Ccdc88a, Clip3, Zcchc18, Chd3 and Itm2a) that was significantly upregulated in T cell-dependent non-VH11 CLL compared with T cell-independent VH11/Vk14 or mutated IgH.TEμ CLL.