Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies
| Autor: | Nathan Singh, Marco Ruella, Sarah K. Tasian, Mathieu Quesnel-Vallieres, Zhiwei Ang, Rawan Shraim, Sisi Zheng, Kristen W. Lynch, David A Hottman, Mukta Asnani, Ammar S. Naqvi, Maureen M. O'Brien, Carolin Schmidt, Manuel Torres-Diz, Katharina E. Hayer, Asen Bagashev, Yoseph Barash, Susan R. Rheingold, John Chukinas, Andrei Thomas-Tikhonenko, Elisabeth Gillespie, Deanne Taylor |
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| Rok vydání: | 2022 |
| Předmět: |
Gene isoform
Messenger RNA Sialic Acid Binding Ig-like Lectin 2 General Medicine Precursor Cell Lymphoblastic Leukemia-Lymphoma Biology medicine.disease In the Spotlight Epitope Epitopes Leukemia Exon Downregulation and upregulation immune system diseases hemic and lymphatic diseases RNA splicing medicine Cancer research Humans Inotuzumab Ozogamicin splice Immunotherapy Antigenic Drift and Shift Child |
| Zdroj: | Blood Cancer Discov |
| ISSN: | 2643-3249 2643-3230 |
| Popis: | Downregulation of surface epitopes causes postimmunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Here we demonstrate that mRNA encoding CD22 undergoes aberrant splicing in B-ALL. We describe the plasma membrane–bound CD22 Δex5–6 splice isoform, which is resistant to chimeric antigen receptor (CAR) T cells targeting the third immunoglobulin-like domain of CD22. We also describe splice variants skipping the AUG-containing exon 2 and failing to produce any identifiable protein, thereby defining an event that is rate limiting for epitope presentation. Indeed, forcing exon 2 skipping with morpholino oligonucleotides reduced CD22 protein expression and conferred resistance to the CD22-directed antibody–drug conjugate inotuzumab ozogamicin in vitro. Furthermore, among inotuzumab-treated pediatric patients with B-ALL, we identified one nonresponder in whose leukemic blasts Δex2 isoforms comprised the majority of CD22 transcripts. In a second patient, a sharp reduction in CD22 protein levels during relapse was driven entirely by increased CD22 exon 2 skipping. Thus, dysregulated CD22 splicing is a major mechanism of epitope downregulation and ensuing resistance to immunotherapy. Significance: The mechanism(s) underlying downregulation of surface CD22 following CD22-directed immunotherapy remains underexplored. Our biochemical and correlative studies demonstrate that in B-ALL, CD22 expression levels are controlled by inclusion/skipping of CD22 exon 2. Thus, aberrant splicing of CD22 is an important driver/biomarker of de novo and acquired resistance to CD22-directed immunotherapies. See related commentary by Bourcier and Abdel-Wahab, p. 87. This article is highlighted in the In This Issue feature, p. 85. |
| Databáze: | OpenAIRE |
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