CD22 Exon 12 Deletion as an Independent Predictor of Poor Treatment Outcomes in B-ALL

SIMPLE SUMMARY: We previously reported that cancer cells from the most common type of childhood cancer, namely, a form of acute leukemia known as B-ALL, are characterized by an abnormality known as CD22 exon 12 deletion. The purpose of the present study was to evaluate the clinical significance of the CD22 exon 12 deletion. Our findings provide the first evidence that CD22 exon 12 deletion is associated with a poor treatment outcome in B-ALL. The reported results also support the notion that the further evaluation of the clinical potential of new strategies targeting this abnormality in B-ALL is warranted. ABSTRACT: We previously reported a splicing defect (CD22ΔE12) associated with the deletion of exon 12 of the inhibitory co-receptor CD22 (Siglec-2) in leukemia cells from patients with CD19(+) B-precursor acute lymphoblastic leukemia (B-ALL). CD22ΔE12 causes a truncating frameshift mutation and yields a dysfunctional CD22 protein that lacks most of the cytoplasmic domain required for its inhibitory function, and it is associated with aggressive in vivo growth of human B-ALL cells in mouse xenograft models. Although CD22ΔE12 with selective reduction of CD22 exon 12 (CD22E12) levels was detected in a high percentage of newly diagnosed as well as relapsed B-ALL patients, its clinical significance remains unknown. We hypothesized that B-ALL patients with very low levels of wildtype CD22 would exhibit a more aggressive disease with a worse prognosis because the missing inhibitory function of the truncated CD22 molecules could not be adequately compensated by competing wildtype CD22. Here, we demonstrate that newly diagnosed B-ALL patients with very low levels of residual wildtype CD22 (“CD22E12(low)”), as measured by RNAseq-based CD22E12 mRNA levels, have significantly worse leukemia-free survival (LFS) as well as overall survival (OS) than other B-ALL patients. CD22E12(low) status was identified as a poor prognostic indicator in both univariate and multivariate Cox proportional hazards models. CD22E12(low) status at presentation shows clinical potential as a poor prognostic biomarker that may guide the early allocation of risk-adjusted, patient-tailored treatment regimens and refine risk classification in high-risk B-ALL.