{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T17:25:19Z","timestamp":1783790719141,"version":"3.55.0"},"reference-count":33,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,7,24]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with high efficacy in lymphoid malignancies. It targets the B-cell surface protein CD22, which is expressed in most B-cell acute lymphoblastic leukemia (B-ALL) cases, albeit with variable intensity. However, factors governing CD22 expression and thus leukemia sensitivity to InO remain incompletely understood. Using multiomic characterization of 196 human B-ALL samples, coupled with ex vivo InO sensitivity profiling, we showed that early leukemia differentiation arrest at the pre\u2013pro-B stage is associated with resistance to InO. Screening of 1639 transcription factor genes identified early B-cell factor 1 (EBF1) as a key regulator of CD22 expression (false discovery rate of 7.1 \u00d7 10\u22124). When comparing the assay for transposase-accessible chromatin with sequencing profiling results of the most InO-sensitive and -resistant cases (50% lethal concentration &amp;lt;10th vs &amp;gt;90th percentile, n = 18), the binding motif for EBF1 was strikingly enriched in regions with differential open chromatin status (P = 8 \u00d7 10\u2212174). CRISPR interference targeting EBF1 binding sites at the CD22 locus led to an \u223c50-fold reduction in cell surface CD22 expression and, consequently, an \u223c22-fold increase in InO resistance in ALL cell lines. Interestingly, within BCR::ABL1 ALL, we observed intrasubtype heterogeneity linked to EBF1 transcriptional downregulation (P = 1.1 \u00d7 10\u221215) and\/or somatic alteration (P = .004), which led to reduced CD22 expression (P = 8.3 \u00d7 10\u221211) and ex vivo and in vivo resistance to InO. Collectively, these findings point to the direct impact of EBF1 on CD22 expression during B-cell development, which, in turn, contributes to interpatient variability in InO response, even within the same subtype of B-ALL.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2024028215","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T16:59:29Z","timestamp":1748451569000},"page":"471-481","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":7,"title":["Differentiation-dependent EBF1 activity determines <i>CD22<\/i> transcription and leukemia sensitivity to inotuzumab ozogamicin"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-3647","authenticated-orcid":false,"given":"Carolin S.","family":"Escherich","sequence":"first","affiliation":[{"name":"1Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children\u2019s Research Hospital, 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