{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T17:39:53Z","timestamp":1776447593555,"version":"3.51.2"},"posted":{"date-parts":[[2026,4,14]]},"group-title":"Cell Biology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"UCSF-California Institute for Regenerative Medicine Scholars Training Program","award":["EDUC4-12812"],"award-info":[{"award-number":["EDUC4-12812"]}]},{"DOI":"10.13039\/100023581","name":"National Science Foundation Graduate Research Fellowship Program","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100023581","id-type":"DOI","asserted-by":"crossref"}]},{"name":"UCSF Center for Maternal-Fetal Precision Medicine"},{"name":"NIH Director\u2019s New Innovator Award","award":["DP2- HL185102"],"award-info":[{"award-number":["DP2- HL185102"]}]},{"name":"UCSF Catalyst Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  First-generation genome editing therapies have largely focused on correcting or compensating for pathogenic variants. However, as these approaches enter the clinic, emerging biological constraints limit maximal therapeutic impact. Because globin genes are activated late during erythroid differentiation, genome-corrected hematopoietic stem and progenitor cells (HSPCs) gain little selective advantage in the bone marrow. Here, we establish a strategy that links therapeutic genome edits to an erythroid fitness-enhancing allele to amplify the output of clinically relevant cells. We develop a multiplex base editing strategy that couples fetal hemoglobin (HbF) reactivation with erythroid lineage expansion. Introduction of a naturally occurring erythropoietin receptor truncation (\n                  <jats:italic>tEPOR<\/jats:italic>\n                  ) associated with benign erythrocytosis increased erythroid cell production without impairing viability or differentiation. Combinatorial editing of\n                  <jats:italic>tEPOR<\/jats:italic>\n                  together with the\n                  <jats:italic>BCL11A<\/jats:italic>\n                  erythroid enhancer and\n                  <jats:italic>HBG1\/2<\/jats:italic>\n                  promoters in healthy donor, sickle cell disease, and \u03b2-thalassemia HSPCs synergistically increased erythroid proliferation and HbF expression beyond single base-edited or Casgevy-treated controls. Multiplex base-edited HSPCs retained long-term lineage repopulation and engraftment capacity\n                  <jats:italic>in vivo<\/jats:italic>\n                  , establishing a modular strategy that pairs disease correction with lineage amplification to improve therapeutic potency.\n                <\/jats:p>","DOI":"10.64898\/2026.04.13.718029","type":"posted-content","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T07:15:11Z","timestamp":1776237311000},"source":"Crossref","is-referenced-by-count":0,"title":["Combinatorial base editing couples disease correction with lineage amplification in hematopoietic stem and progenitor cells"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4306-8643","authenticated-orcid":false,"given":"Kun","family":"Jia","sequence":"first","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Soupene","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Benioff Children\u2019s Hospital Oakland, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roshani","family":"Sinha","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin J.","family":"Lesch","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3560-0290","authenticated-orcid":false,"given":"Michael A.","family":"Pendergast","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6075-8687","authenticated-orcid":false,"given":"Rachel","family":"Choi","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1595-8759","authenticated-orcid":false,"given":"Elisabetta M.","family":"Foppiani","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5571-8713","authenticated-orcid":false,"given":"Zachary","family":"Kostamo","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3863-1548","authenticated-orcid":false,"given":"Simon N.","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3801-7276","authenticated-orcid":false,"given":"Devesh","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinjie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1265-624X","authenticated-orcid":false,"given":"Marco","family":"Cordero","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6515-4559","authenticated-orcid":false,"given":"Mark C.","family":"Walters","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Benioff Children\u2019s Hospital Oakland, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5232-809X","authenticated-orcid":false,"given":"Tippi C.","family":"MacKenzie","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2837-2255","authenticated-orcid":false,"given":"Vivien A.","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Aflac Cancer & Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8198-5010","authenticated-orcid":false,"given":"M. Kyle","family":"Cromer","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Eli & Edythe Broad Center for Regeneration Medicine, University of California, San Francisco, San Francisco, CA, USA"},{"name":"Department of Bioengineering & Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041709400817000_2026.04.13.718029v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2031054"},{"key":"2026041709400817000_2026.04.13.718029v1.2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004232"},{"key":"2026041709400817000_2026.04.13.718029v1.3","doi-asserted-by":"crossref","unstructured":"Chakraborty, N.G. , Bilgrami, S. , Maness, L.J. , Guo, C. , Perez-Diez, A. , Mukherji, B. , and Tutschka, P . (1999). Myeloablative chemotherapy with autologous peripheral blood stem cell transplantation for metastatic breast cancer: immunologic consequences affecting clinical outcome.","DOI":"10.1038\/sj.bmt.1701999"},{"key":"2026041709400817000_2026.04.13.718029v1.4","doi-asserted-by":"publisher","DOI":"10.1586\/ehm.11.39"},{"key":"2026041709400817000_2026.04.13.718029v1.5","doi-asserted-by":"publisher","DOI":"10.3389\/fgeed.2022.1050507"},{"key":"2026041709400817000_2026.04.13.718029v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01377-0"},{"key":"2026041709400817000_2026.04.13.718029v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4192"},{"key":"2026041709400817000_2026.04.13.718029v1.8","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2024015574"},{"key":"2026041709400817000_2026.04.13.718029v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0059-1"},{"key":"2026041709400817000_2026.04.13.718029v1.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2501277"},{"key":"2026041709400817000_2026.04.13.718029v1.11","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2023.29263.bfs"},{"key":"2026041709400817000_2026.04.13.718029v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-026-10342-9"},{"key":"2026041709400817000_2026.04.13.718029v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03609-w"},{"key":"2026041709400817000_2026.04.13.718029v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0790-y"},{"key":"2026041709400817000_2026.04.13.718029v1.15","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2215643"},{"key":"2026041709400817000_2026.04.13.718029v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13007-6"},{"key":"2026041709400817000_2026.04.13.718029v1.17","doi-asserted-by":"publisher","DOI":"10.1101\/2024.03.05.582637"},{"key":"2026041709400817000_2026.04.13.718029v1.18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.10.4495"},{"key":"2026041709400817000_2026.04.13.718029v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2023.10.007"},{"key":"2026041709400817000_2026.04.13.718029v1.20","doi-asserted-by":"crossref","unstructured":"Uchida, N. , Ferrara, F. , Drysdale, C.M. , Yapundich, M. , Gamer, J. , Nassehi, T. , Dinicola, J. , Shibata, Y. , Wielgosz, M. , Kim, Y.-S. , et al. (2021). Sustained fetal hemoglobin induction in vivo is achieved by BCL11A interference and coexpressed truncated erythropoietin receptor.","DOI":"10.1126\/scitranslmed.abb0411"},{"key":"2026041709400817000_2026.04.13.718029v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-024-01222-6"},{"key":"2026041709400817000_2026.04.13.718029v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35508-7"},{"key":"2026041709400817000_2026.04.13.718029v1.23","unstructured":"Taolin Yi, B. , Zhang, J. , Miura, O. , and lhle, J.N. Hematopoietic Cell Phosphatase Associates With Erythropoietin (Epo) Receptor After Epo-Induced Receptor Tyrosine Phosphorylation: Identification of Potential Binding Sites."},{"key":"2026041709400817000_2026.04.13.718029v1.24","doi-asserted-by":"crossref","unstructured":"Klingmoller, U. , Lorenz, U. , Cantley, L.C. , Neel, B.G. , and Lodish, H.F. (1995). Specific Recruitment of SH-PTP1 to the Erythropoietin Receptor Causes Inactivation of JAK2 and Termination of Proliferative Signals.","DOI":"10.1016\/0092-8674(95)90351-8"},{"key":"2026041709400817000_2026.04.13.718029v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4172"},{"key":"2026041709400817000_2026.04.13.718029v1.26","doi-asserted-by":"publisher","DOI":"10.1089\/crispr.2018.0014"},{"key":"2026041709400817000_2026.04.13.718029v1.27","doi-asserted-by":"crossref","first-page":"104018","DOI":"10.1016\/j.xpro.2025.104018","article-title":"Protocol for efficient CRISPR\/AAV-mediated genome editing and erythroid differentiation of human hematopoietic stem and progenitor cells","volume":"6","year":"2025","journal-title":"STAR Protoc"},{"key":"2026041709400817000_2026.04.13.718029v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.02.011"},{"key":"2026041709400817000_2026.04.13.718029v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2014.64"},{"key":"2026041709400817000_2026.04.13.718029v1.30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56239-5"},{"key":"2026041709400817000_2026.04.13.718029v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45969-7"},{"key":"2026041709400817000_2026.04.13.718029v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01284-y"},{"key":"2026041709400817000_2026.04.13.718029v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01888-4"},{"key":"2026041709400817000_2026.04.13.718029v1.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102157"},{"key":"2026041709400817000_2026.04.13.718029v1.35","doi-asserted-by":"publisher","DOI":"10.1093\/jmcb\/mjad018"},{"key":"2026041709400817000_2026.04.13.718029v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.02.010"},{"key":"2026041709400817000_2026.04.13.718029v1.37","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2504835"},{"key":"2026041709400817000_2026.04.13.718029v1.38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309673"},{"key":"2026041709400817000_2026.04.13.718029v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2014.12.005"},{"key":"2026041709400817000_2026.04.13.718029v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2024.101334"},{"key":"2026041709400817000_2026.04.13.718029v1.41","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abf2444"},{"key":"2026041709400817000_2026.04.13.718029v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43413-w"},{"key":"2026041709400817000_2026.04.13.718029v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.02.019"},{"key":"2026041709400817000_2026.04.13.718029v1.44","doi-asserted-by":"crossref","unstructured":"Hu, Z. , Van Rooijen, N. , and Yang, Y.-G. (2011). Macrophages prevent human red blood cell reconstitution in immunodeficient mice. 10.1182\/blood.","DOI":"10.1182\/blood-2010-11-321414"},{"key":"2026041709400817000_2026.04.13.718029v1.45","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.20023"},{"key":"2026041709400817000_2026.04.13.718029v1.46","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2024015574"},{"key":"2026041709400817000_2026.04.13.718029v1.47","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2025017838"},{"key":"2026041709400817000_2026.04.13.718029v1.48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-02-550327"},{"key":"2026041709400817000_2026.04.13.718029v1.49","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06496-5"},{"key":"2026041709400817000_2026.04.13.718029v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2024.101343"},{"key":"2026041709400817000_2026.04.13.718029v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-59713-2"},{"key":"2026041709400817000_2026.04.13.718029v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102376"},{"key":"2026041709400817000_2026.04.13.718029v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-45969-7"},{"key":"2026041709400817000_2026.04.13.718029v1.54","doi-asserted-by":"publisher","DOI":"10.1101\/2025.05.09.653165"},{"key":"2026041709400817000_2026.04.13.718029v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-023-01434-7"},{"key":"2026041709400817000_2026.04.13.718029v1.56","doi-asserted-by":"publisher","DOI":"10.1089\/hgtb.2011.034"},{"key":"2026041709400817000_2026.04.13.718029v1.57","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku936"},{"key":"2026041709400817000_2026.04.13.718029v1.58","doi-asserted-by":"publisher","DOI":"10.1089\/crispr.2021.0113"},{"key":"2026041709400817000_2026.04.13.718029v1.59","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-023-01073-7"},{"key":"2026041709400817000_2026.04.13.718029v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.115141"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.13.718029","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:40:21Z","timestamp":1776444021000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.13.718029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":60,"URL":"https:\/\/doi.org\/10.64898\/2026.04.13.718029","relation":{},"subject":[],"published":{"date-parts":[[2026,4,14]]},"subtype":"preprint"}}