Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2022
- Source ID
- 10.1158/2643-3230.bcd-21-0087
Entities
People
- Ammar S Naqvi
- Andrei Thomas-Tikhonenko
- Asen Bagashev
- Carolin Schmidt
- David A. Hottman
- Deanne M. Taylor
- Elisabeth Gillespie
- John Chukinas
- Katharina E. Hayer
- Kristen W. Lynch
- Manuel Torres-Diz
- Marco Ruella
- Mathieu Quesnel-vallières
- Maureen M O'Brien
- Mukta Asnani
- Nathan Singh
- Rawan Shraim
- Sarah K. Tasian
- Sijin Zheng
- Susan R Rheingold
- Yoseph Barash
- Zhiwei Ang
Organizations
- Children's Hospital of Philadelphia
- National Cancer Institute
- Pfizer
- Stand Up to Cancer
- United States Department of Defense
- University of Cincinnati
- University of Pennsylvania
- V Foundation for Cancer Research