Single-cell genomics to comprehensively understand healthy B-cell maturation and transformation to chronic lymphocytic leukemia

Projektinformationen

BCLLatlas

ID Finanzhilfevereinbarung: 810287

DOI

10.3030/810287

Projekt abgeschlossen

EK-Unterschriftsdatum 29 März 2019

Startdatum 1 April 2019

Enddatum 31 Dezember 2025

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 8 333 331,00

EU-Beitrag

€ 8 333 331,00

Koordiniert durch

CONSORCIO PARA LA EXPLOTACION DEL CENTRO NACIONAL DE ANALISIS GENOMICO
Spain

Periodic Reporting for period 4 - BCLLatlas (Single-cell genomics to comprehensively understand healthy B-cell maturation and transformation to chronic lymphocytic leukemia)

Berichtszeitraum: 2023-10-01 bis 2025-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The overall objective of the BCLL@las project is to make major headway towards the understanding of chronic lymphocytic leukaemia (CLL), one of the major malignacies in over-60-year olds. With an ageing population the incidence of this disease is certain to increase. The questions are, how does CLL develop, what are the triggers, how does it respond to treatment, can outcome be predicted early and could better treament regimes be established based on this knowledge? To advance on this we have formulated four main aims: 1: A comprehensive atlas of B-cell maturation, 2: Understanding neoplastic transformation through pre-malignant clonal B-cell proliferation, 3: Deciphering the cellular diversity and clonal architecture of CLL, and 4: Single-cell dynamics of CLL during disease evolution and therapy. The most advanced technologies for the characterisation of the cells and cell types involved are applied comprehensively, which allows shining light on this problem with unprecedented resolution.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

Up until now we have worked on setting up methods and technologies that were not available to us at the beginning of the project. These were methods that were presented recently or were required by us. They were implemented, stress-tested and in many instances subjected to extensive benchmarking. We obtained tonsils from donors that covered three age groups (pediatric, young and old adults), and both sexes and used scRNA-seq (gene expression), scATAC-seq (chromatin accessibility), 10x multiome (joint scRNA-seq and scATAC-seq), CITE-seq (~200 protein surface markers and whole transcriptome), and spatial transcriptomics. Taken together, we profiled over 350,000 cells, which clustered into over 80 cell types and states. To our knowledge, this gives the highest resolution atlas of the hematopoietic cell lineage to date.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We have resolved the hematopoietic lineage into 80 distinct cell types and states and were able to resolve the transitions between cell types and states. A second big achievement has been the dissection of the genetic and transcriptional landscape of the Richter transformation in CLL. Richter clones are aggressive and associated with fatal outcome. We have found that clones that represent the bulk of the cells in the Richter transformation are detectable in some instances more than a decade earlier. However, they are not cleared by early rounds of therapy.

Summary for publication

1.6 Major Achievements - Circos Plot