Cover Images & Graphical Abstracts

Cancer Discovery Peer-reviewed Journal Cover - December 2015
Chimeric antigen receptor T-cell therapy targeting CD19 (CART-19) is clinically active in pediatric B-cell acute lymphoblastic leukemia
(B-ALL), but loss of the CD19 epitope has been implicated in tumor relapse. Sotillo and colleagues compared paired CD19-positive,
pre–CART-19 and CD19-negative, post–CART-19 relapsed pediatric B-ALL samples and found hemizygous deletion of CD19 and mutations affecting CD19 exon 2 in a subset of relapsed tumors. Alternatively spliced CD19
transcripts were also specifically identified in relapsed samples, including a splice variant with exon 2 skipping (CD19 Δex2) that resulted in expression of a functional truncated protein. CD19 Δex2 expression provided a proliferative advantage and partially rescued the effects of CD19 loss. In addition, CD19 Δex2–expressing cells remained viable upon CART-19 exposure, suggesting that alternative splicing can lead to epitope loss and evasion from CAR T-cell therapy. For details, please see the article by Sotillo and colleagues on page 1282.
Cover photograph: Four-channel confocal microscopy of a Nalm-6 B-ALL cell engineered to express the immunotherapy-resistant CD19 exon 2 variant 105R. The corresponding CD19 protein is rendered in green and shows colocalization with the endoplasmic reticulum marker calnexin (magenta), as evidenced by the chromatic shift to white at the colocalization sites. The plasma membrane is depicted in red (wheat germ agglutinin), and the cell nucleus is counterstained with DAPI (4′,6-diamidino-2-phenylindole; blue). The Adobe Photoshop craquelure filter was applied to the image postoverlay. (See related article at e00383-18.) (Copyright © 2018 American Society for Microbiology.)







 
In this issue of Blood Cancer Discovery: Downregulation of surface epitopes, including CD22, causes postimmunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Zheng et al. report that CD22 mRNA is pervasively misspliced in B-ALL cell lines and primary samples. Some misspliced isoforms still encode plasma membrane–bound CD22 variants, while others lack the start codon in exon 2 and are noncoding. These exon 2–skipping isoforms are prevalent in high-risk B-ALL patients treated with the CD22-directed antibody–drug conjugate inotuzumab, where they correlate with low CD22 surface expression and are likely to account for treatment failure in two cases. Thus, aberrant CD22 splicing is an important mechanism of resistance to immunotherapy.








 

 

 

In this issue of Blood, Ang et al show that human CD20 messenger RNA (mRNA) undergoes alternative splicing to generate distinct 5' untranslated region (5'-UTR) variants, which determine the cell-surface CD20 levels in malignant B cells and the interpatient variability in the expression of this therapeutic target. These variants can also be used as an escape mechanism from anti-CD20 therapies.
Cell Reports paper highlights:
• The hallmark of pediatric high-grade gliomas is pervasive mis-splicing of microexons
• Transcripts encoding the neuronal cell adhesion molecule (NRCAM) skip exons 5 and 19
• Δex5Δex19, but not full-length, NRCAM drives tumor growth in orthotopic glioma models
• Δex5Δex19 NRCAM-selective mAb enables killing by T cells expressing the Fc receptor