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

Project Information

BCLLatlas

Grant agreement ID: 810287

DOI

10.3030/810287

Project closed

EC signature date 29 March 2019

Start date 1 April 2019

End date 31 December 2025

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 8 333 331,00

EU contribution

€ 8 333 331,00

Coordinated by

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)

Reporting period: 2023-10-01 to 2025-03-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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