Single-cell epigenetic and transcriptomic states across the continuum of monoclonal B cell lymphocytosis to chronic lymphocytic leukemia
BACKGROUND: Chronic lymphocytic leukemia (CLL) develops from physiologic B cells through low- and high-count monoclonal B cell lymphocytosis (LC-/HC-MBL). The timing and nature of early B cell expansion and molecular evolution remain unclear, limiting prediction of progression. RESULTS: Using multi-omics single-cell sequencing integrating chromatin accessibility, transcriptional, proteomic, and mitochondrial DNA (mtDNA) profiles across normal B cells, LC-/HC-MBL, and CLL, we delineate clonal relationships and evolutionary trajectories. Our data reveals subclonal, epigenetic, and transcriptomic stability during the transition from HC-MBL to CLL, suggesting a continuous disease spectrum rather than distinct evolutionary phases. CLL-like molecular states already exist in LC-MBL and, along with individual-specific heterogeneity across HC-MBL/CLL, are linked with disease progression. Finally, we find genetic evidence for a shared progenitor between physiologic and monoclonal B cells. CONCLUSIONS: These results position LC-MBL as a key inflection point in early CLL pathogenesis and a potential target for progression risk prediction or preventive strategies.
Authors
- Stacey M. Fernandes (ORCID: https://orcid.org/0000-0002-5061-5199)
- Adi Nagler (ORCID: https://orcid.org/0000-0003-2127-5938)
- Livius Penter (ORCID: https://orcid.org/0000-0002-9060-0207)
- Kenneth J. Livak (ORCID: https://orcid.org/0000-0001-9105-5856)
- Matthew Steven Davids (ORCID: https://orcid.org/0000-0003-4529-2003)
- Lars Bullinger
- D M Dorfman
- Catherine A. Wu (ORCID: https://orcid.org/0000-0002-6123-4420)
- Leif S. Ludwig (ORCID: https://orcid.org/0000-0002-2916-2164)
- S Li
- Anja C. Rathgeber (ORCID: https://orcid.org/0000-0003-3264-1040)
- Jennifer R. Brown
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- German Cancer Research Center (DE)
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- Humboldt-Universität zu Berlin (DE)
- National Center for Tumor Diseases (DE)
- Dana-Farber Cancer Institute (US)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Massachusetts Institute of Technology (US)
- Freie Universität Berlin (DE)
Publication Details
- Journal
- Genome biology
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1186/s13059-026-04072-4
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- American Society of Hematology
- Leukemia and Lymphoma Society
- Parker Institute for Cancer Immunotherapy
- Deutsche Forschungsgemeinschaft
- Charité – Universitätsmedizin Berlin
- Else Kröner-Fresenius-Stiftung
- Deutsche Krebshilfe
- National Cancer Institute