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Modulation of CD22 protein expression in childhood leukemia by pervasive splicing aberrations: implications for CD22-directed immunotherapies

Authors: 
Zheng S, Gillespie E, Naqvi AS, Hayer KE, Ang Z, Torres-Diz M, Quesnel-Vallieres M, Hottman DA, Bagashev A, Chukinas J, Schmidt C, Asnani M, Shraim R, Taylor DM, Rheingold SR, O'Brien MM, Singh N, Lynch KW, Ruella M, Barash Y, Tasian SK, Thomas-Tikhonenko A
Citation: 
Blood Cancer Discov. 2022:3(2):103–15. doi:10.1158/2643-3230.BCD-21-0087
Abstract: 
Downregulation of surface epitopes causes post-immunotherapy 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 resistant to 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; therefore, this event could be 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 in vitro. Furthermore, among inotuzumab-treated pediatric B-ALL patients, we identified one non-responder in whose 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.
Epub: 
Not Epub
Organism or Cell Type: 
cell culture