Identification of leukemic and pre-leukemic stem cells by clonal tracking from single-cell transcriptomics

Cancer stem cells drive disease progression and relapse in many types of cancer. Despite this, a thorough characterization of these cells remains elusive and with it the ability to eradicate cancer at its source. In acute myeloid leukemia (AML), leukemic stem cells (LSCs) underlie mortality but are difficult to isolate due to their low abundance and high similarity to healthy hematopoietic stem cells (HSCs). Here, we demonstrate that LSCs, HSCs, and pre-leukemic stem cells can be identified and molecularly profiled by combining single-cell transcriptomics with lineage tracing using both nuclear and mitochondrial somatic variants. While mutational status discriminates between healthy and cancerous cells, gene expression distinguishes stem cells and progenitor cell populations. Our approach enables the identification of LSC-specific gene expression programs and the characterization of differentiation blocks induced by leukemic mutations. Taken together, we demonstrate the power of single-cell multi-omic approaches in characterizing cancer stem cells.This project was financially supported by the Deutsche José Carreras Leukämie Stiftung grant DJCLS 20R/2017 (to L.V., S.H., L.M.S., and A.T.), the Emerson foundation grant 643577 (to L.V. and L.M.S.) and the German Bundesministerium für Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin “LeukoSyStem” (FKZ 01ZX1911D to L.V., S.H., and S.R). Contributions by S.R. were further supported by Emmy Noether Fellowship RA 3166/1-1 (DFG). Contributions by C.P. were supported by a Max-Eder Grant (German Cancer Aid 70111531). Contributions by D.N., J.C.J., W.K.H., and T.B. were supported by the Gutermuth Foundation, the H.W. & J. Hector fund, Baden-Württemberg, and the Dr. Rolf M. Schwiete Fund, Mannheim. D.N. is an endowed professor of the Deutsche José Carreras Leukämie Stiftung (DJCLS H 03/01

Computed tomography versus invasive coronary angiography: design and methods of the pragmatic randomised multicentre DISCHARGE trial

Objectives More than 3.5 million invasive coronary angiographies (ICA) are performed in Europe annually. Approximately 2 million of these invasive procedures might be reduced by noninvasive tests because no coronary intervention is performed. Computed tomography (CT) is the most accurate noninvasive test for detection and exclusion of coronary artery disease (CAD). To investigate the comparative effectiveness of CT and ICA, we designed the European pragmatic multicentre DISCHARGE trial funded by the 7th Framework Programme of the European Union (EC-GA 603266). Methods In this trial, patients with a low-to-intermediate pretest probability (10–60 %) of suspected CAD and a clinical indication for ICA because of stable chest pain will be randomised in a 1-to-1 ratio to CT or ICA. CT and ICA findings guide subsequent management decisions by the local heart teams according to current evidence and European guidelines. Results Major adverse cardiovascular events (MACE) defined as cardiovascular death, myocardial infarction and stroke as a composite endpoint will be the primary outcome measure. Secondary and other outcomes include cost-effectiveness, radiation exposure, health-related quality of life (HRQoL), socioeconomic status, lifestyle, adverse events related to CT/ICA, and gender differences. Conclusions The DISCHARGE trial will assess the comparative effectiveness of CT and ICA