Single-cell epigenetic and transcriptomic states across the continuum of monoclonal B cell lymphocytosis to chronic lymphocytic leukemia

Rathgeber, Anja C.; Fernandes, Stacey M.; Nagler, Adi; Li, Shuqiang; Dorfman, David M.; Bullinger, Lars; Davids, Matthew S.; Brown, Jennifer R.; Livak, Kenneth J.; Ludwig, Leif S.; Wu, Catherine J.; Penter, Livius

Single-cell epigenetic and transcriptomic states across the continuum of monoclonal B cell lymphocytosis to chronic lymphocytic leukemia

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Item Type:	Article
Title:	Single-cell epigenetic and transcriptomic states across the continuum of monoclonal B cell lymphocytosis to chronic lymphocytic leukemia
Creators Name:	Rathgeber, Anja C., Fernandes, Stacey M., Nagler, Adi, Li, Shuqiang, Dorfman, David M., Bullinger, Lars, Davids, Matthew S., Brown, Jennifer R., Livak, Kenneth J., Ludwig, Leif S., Wu, Catherine J. and Penter, Livius
Abstract:	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.
Keywords:	Monoclonal B Cell Lymphocytosis, Chronic Lymphocytic Leukemia, Mitochondrial DNA Mutations, Lineage-Tracing, Multi-Omics
Source:	Genome Biology
ISSN:	1474-760X
Publisher:	BioMed Central
Date:	15 April 2026
Official Publication:	https://doi.org/10.1186/s13059-026-04072-4
PubMed:	View item in PubMed
Related to:	URL URL Type https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295489 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295490 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295491 External Dataset https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA1254962 External Dataset https://github.com/AnjaCaRa/sc_MBL-CLL-transition_manuscript Software

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