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Issue 2, 2015
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CD22ΔE12 as a molecular target for corrective repair using RNA trans-splicing: anti-leukemic activity of a rationally designed RNA trans-splicing molecule

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Abstract

Our recent studies have demonstrated that the CD22 exon 12 deletion (CD22ΔE12) is a characteristic genetic defect of therapy-refractory clones in pediatric B-precursor acute lymphoblastic leukemia (BPL) and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory pediatric BPL. The purpose of the present study was to further evaluate the biologic significance of the CD22ΔE12 molecular lesion and determine if it could serve as a molecular target for corrective repair using RNA trans-splicing therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22ΔE12 genetic defect. We provide experimental evidence that the correction of the CD22ΔE12 genetic defect in human CD22ΔE12+ BPL cells using a rationally designed CD22 RNA trans-splicing molecule (RTM) caused a pronounced reduction of their clonogenicity. The RTM-mediated correction replaced the downstream mutation-rich segment of Intron 12 and remaining segments of the mutant CD22 pre-mRNA with wildtype CD22 exons 10–14, thereby preventing the generation of the cis-spliced aberrant CD22ΔE12 product. The anti-leukemic activity of this RTM against BPL xenograft clones derived from CD22ΔE12+ leukemia patients provides the preclinical proof-of-concept that correcting the CD22ΔE12 defect with rationally designed CD22 RTMs may provide the foundation for therapeutic innovations that are needed for successful treatment of high-risk and relapsed BPL patients.

Graphical abstract: CD22ΔE12 as a molecular target for corrective repair using RNA trans-splicing: anti-leukemic activity of a rationally designed RNA trans-splicing molecule

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Publication details

The article was received on 26 Sep 2014, accepted on 22 Dec 2014 and first published on 23 Dec 2014


Article type: Paper
DOI: 10.1039/C4IB00221K
Citation: Integr. Biol., 2015,7, 237-249

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