Differentiation-dependent EBF1 activity determines CD22 transcription and leukemia sensitivity to inotuzumab ozogamicin
Year: 2025
Type: article
Abstract: ABSTRACT: 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-pro-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 × 10-4). When comparing the assay for transposase-accessible chromatin with sequencing profiling results of the most InO-sensitive and -resistant cases (50% lethal concentration <10th vs >90th percentile, n = 18), the binding motif for EBF1 was strikingly enriched in regions with differential open chromatin status (P = 8 × 10-174). CRISPR interference targeting EBF1 binding sites at the CD22 locus led to an ∼50-fold reduction in cell surface CD22 expression and, consequently, an ∼22-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 × 10-15) and/or somatic alteration (P = .004), which led to reduced CD22 expression (P = 8.3 × 10-11) 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.
Source: Blood
Authors: Carolin S. Escherich, Zhenhua Li, Kelly R. Barnett, Yizhen Li, Megan Walker, Satoshi Yoshimura, Wenjian Yang, Xin Huang, Jiyang Yu, Wendy Stock, Elisabeth Paietta, Marina Y. Konopleva, Steven M. Kornblau, Elias Jabbour, Mark R. Litzow, Hiroto Inaba, Ching-Hon Pui, Mignon L. Loh, William E. Evans, Daniel Savic, Jun J. Yang
Institutions: St. Jude Children's Research Hospital, Heinrich Heine University Düsseldorf, Soochow University, Children's Hospital of Suzhou University, University of Chicago, Albert Einstein College of Medicine, Montefiore Medical Center, The University of Texas MD Anderson Cancer Center, Mayo Clinic, Seattle Children's Hospital, University of Washington, Fred Hutch Cancer Center
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Genetische Einflussfaktoren die zur Resistenz gegen Inotuzumabozogamicin bei Akuter Lymphatischer Leukämie beitragen, G1744533847, ECOG-ACRIN Network Group Operations Center, MINORITY-BASED COMMUNITY ONCOLOGY PROGRAM, G2484864540, G2490302200, G2554726104, G2819266960, G2954099590, G307654227, G3100437649, G425884651, G4766096375, G6705915398, G9000027531, G9000082729, G9000106591, G9000123384, G9000280145, G9000299658, Cancer Center Support Grant (CCSG)
OpenAlex ID: W4410806515