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The timing and nature of early B cell expansion and molecular evolution remain unclear, limiting prediction of progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13059-026-04072-4","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T04:34:53Z","timestamp":1776227693000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Single-cell epigenetic and transcriptomic states across the continuum of monoclonal B cell lymphocytosis to chronic lymphocytic leukemia"],"prefix":"10.1186","volume":"27","author":[{"given":"Anja C.","family":"Rathgeber","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey M.","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Nagler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Dorfman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Bullinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew S.","family":"Davids","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Livak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leif S.","family":"Ludwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9060-0207","authenticated-orcid":false,"given":"Livius","family":"Penter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"issue":"1","key":"4072_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nrdp.2016.96","volume":"3","author":"TJ Kipps","year":"2017","unstructured":"Kipps TJ, Stevenson FK, Wu CJ, et al. 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The experimental methods of this study comply with the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All participants signed written informed consent, including for publication of sequencing data, prior to any sample collection.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"C.J.W. is an equity holder of BioNTech, Inc, receives research funding from Pharmacyclics, and is a SAB member of Repertoire, Nature\u2019s Toolbox, Aethon Therapeutics, and Adventris. K.J.L. reports equity in Standard BioTools Inc. and serves on the scientific advisory board for MBQ Pharma Inc. L.B. received honoraria from AbbVie, Amgen, Astellas, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Otsuka, Pfizer, Roche, and Sanofi; research funding from Bayer, Jazz Pharmaceuticals.\nM.S.D. has received institutional research funding from AstraZeneca and Ascentage Pharma,; and received personal consulting income from AbbVie, Ascentage Pharma, AstraZeneca, BeOne Medicines, Bristol Myers Squibb, Eli Lilly, Genentech, Genmab, Janssen, Merck, Nuvalent,and Schr\u04e7dinger, and receives royalties from UpToDate. J.R.B. has served as a consultant for Abbvie, Acerta\/Astra-Zeneca, Alloplex Biotherapeutics, BeiGene, Bristol-Myers Squibb, EcoR1, Galapagos NV, Genentech\/Roche, Grifols Worldwide Operations, InnoCare Pharma Inc, Kite Pharma, Loxo\/Lilly, Magnet Biomedicine, Merck, Numab Therapeutics, Nurix Therapeutics, Pfizer, Pharmacyclics; received research funding from BeiGene, Gilead, iOnctura, Loxo\/Lilly, MEI Pharma, Nagoon Therapeutics, and TG Therapeutics; serves on the Data Safety Monitoring Board for Grifols Therapeutics; and receives royalties from UpToDate. The Broad Institute has filed for patents relating to the use of technologies described in this paper, where L.S.L. is named an inventor (US patent applications 17\/251,451 and 17\/928,696). L.S.L is a Guest Editor for Genome Biology\u2019s \u201cLeveraging mitochondria to understand health and disease\u201d collection but was not involved in the editorial process of this manuscript. All other authors do not have any relevant conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"175"}}