The early evolution of chronic clonal lymphocytosis

The early evolution of chronic clonal lymphocytosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The early evolution of chronic clonal lymphocytosis Liran Shlush, Tal Bacharach, Oren Milman, Guy Shemesh, Ofir Raz, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8160900/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Mature B-cell neoplasms often present with chronic clonal lymphocytosis, yet their earliest evolutionary stages and precise origins remain unclear. Using single-cell RNA and paired BCR sequencing with targeted DNA analysis across B-cell differentiation, we identified distinct pathological B-cell states—memory, aged, CLL, and aged-HCL—that only partially aligned with clinical diagnoses. Notably, CLL-like and aged-like expansions were also detected in healthy individuals, revealing both classical MBL and a previously unrecognized “aged-like” MBL. A central finding of this study is that CLL-like programs arise in mono-, oligo-, and polyclonal B cells, indicating that the malignant state emerges before clonal selection. This manuscript uncovers two mechanisms explaining this unusual oligo/polyclonal origin: (1) evidence of autoreactivity through BCR editing in CLL cells, and (2) somatic mutations in hematopoietic stem and progenitor cells that generate oligo/polyclonal B-cell outputs. These results establish pre-leukemic oligo/polyclonal evolution as a widespread precursor to chronic B-cell malignancies. Health sciences/Diseases/Haematological diseases/Haematological cancer/Lymphoma Biological sciences/Immunology/Lymphocytes/B cells Health sciences/Molecular medicine Full Text Additional Declarations There is NO Competing Interest. Ethics approval from the Weizmann Institute of science IRB protocol: 2297-2 - Chracterization of circulating human HSPCs in health and disease (2313-1) Supplementary Files supplementarytables.pdf Supplementary Tables 1-8 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8160900","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":557755217,"identity":"e9c5e835-b6a5-4595-906f-3b30542bd152","order_by":0,"name":"Liran 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Using single-cell RNA and paired BCR sequencing with targeted DNA analysis across B-cell differentiation, we identified distinct pathological B-cell states\u0026mdash;memory, aged, CLL, and aged-HCL\u0026mdash;that only partially aligned with clinical diagnoses. Notably, CLL-like and aged-like expansions were also detected in healthy individuals, revealing both classical MBL and a previously unrecognized \u0026ldquo;aged-like\u0026rdquo; MBL. A central finding of this study is that CLL-like programs arise in mono-, oligo-, and polyclonal B cells, indicating that the malignant state emerges \u003cem\u003ebefore\u003c/em\u003e clonal selection. This manuscript uncovers two mechanisms explaining this unusual oligo/polyclonal origin: (1) evidence of autoreactivity through BCR editing in CLL cells, and (2) somatic mutations in hematopoietic stem and progenitor cells that generate oligo/polyclonal B-cell outputs. 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