{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T03:47:24Z","timestamp":1793850444495,"version":"4.6.1"},"reference-count":27,"publisher":"American Society of Hematology","issue":"1","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/legalcode"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19\u2212 (pre)-leukemic cells represent an \u201cearly progenitor origin-related\u201d mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19\u2212CD22+ cells are found in diagnostic and relapsed bone marrow samples of \u223c70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19\u2212CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19\u2212CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in\u00a0vivo. Our data suggest that preleukemic CD34+CD19\u2212CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19\/CD22 dual targeting as a strategy for reducing CD19\u2212 relapses. The implementation of CD34\/CD19\/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.<\/jats:p>","DOI":"10.1182\/blood.2021014840","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T20:52:36Z","timestamp":1649969556000},"page":"38-44","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":41,"title":["CD34+CD19\u2212CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1442-6216","authenticated-orcid":false,"given":"Clara","family":"Bueno","sequence":"first","affiliation":[{"name":"1Josep Carreras Leukemia Research Institute, Campus Clinic, Barcelona, Spain;"},{"name":"2Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Oncolog\u00eda (CIBER-ONC) and"},{"name":"3Red Espa\u00f1ola de Terapias Avanzadas (TERAV), Redes de Investigaci\u00f3n Cooperativa Orientadas a Resultados en Salud (RICORS RD21\/0017\/0029), Instituto de Salud Carlos III (ISCIII), Madrid, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Barrera","sequence":"additional","affiliation":[{"name":"2Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Oncolog\u00eda (CIBER-ONC) and"},{"name":"4Cancer Research Center (IBMCC-CSIC\/USAL-IBSAL), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca, Salamanca, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6085-2745","authenticated-orcid":false,"given":"Alex","family":"Bataller","sequence":"additional","affiliation":[{"name":"1Josep Carreras Leukemia Research Institute, Campus Clinic, Barcelona, Spain;"},{"name":"5Department of Clinical Hematology, Hospital Clinic of Barcelona, Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4699-6862","authenticated-orcid":false,"given":"Valent\u00edn","family":"Ortiz-Maldonado","sequence":"additional","affiliation":[{"name":"5Department of Clinical Hematology, Hospital Clinic of Barcelona, Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalina","family":"Elliot","sequence":"additional","affiliation":[{"name":"6Department of Paediatrics, Children's Hospital, John Radcliffe Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3116-1646","authenticated-orcid":false,"given":"Sorcha","family":"O\u2019Byrne","sequence":"additional","affiliation":[{"name":"6Department of Paediatrics, Children's Hospital, John Radcliffe Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanlin","family":"Wang","sequence":"additional","affiliation":[{"name":"7MRC (Medical Research 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