TY - JOUR
T1 - Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations
T2 - Implications for CD22-Directed Immunotherapies
AU - Zheng, Sisi
AU - Gillespie, Elisabeth
AU - Naqvi, Ammar S.
AU - Hayer, Katharina E.
AU - Ang, Zhiwei
AU - Torres-Diz, Manuel
AU - Quesnel-Vallières, Mathieu
AU - Hottman, David A.
AU - Bagashev, Asen
AU - Chukinas, John
AU - Schmidt, Carolin
AU - Asnani, Mukta
AU - Shraim, Rawan
AU - Taylor, Deanne M.
AU - Rheingold, Susan R.
AU - O'Brien, Maureen M.
AU - Singh, Nathan
AU - Lynch, Kristen W.
AU - Ruella, Marco
AU - Barash, Yoseph
AU - Tasian, Sarah K.
AU - Thomas-Tikhonenko, Andrei
N1 - Publisher Copyright:
©2021The Authors; Published by the American Association for Cancer Research.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85147460978&partnerID=8YFLogxK
U2 - 10.1158/2643-3230.BCD-21-0087
DO - 10.1158/2643-3230.BCD-21-0087
M3 - Article
C2 - 35015683
AN - SCOPUS:85147460978
SN - 2643-3230
VL - 3
SP - 103
EP - 115
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 2
ER -