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CD22?E12 as a molecular target for corrective repair using RNA trans-splicing: anti-leukemic activity of a rationally designed RNA trans-splicing molecule.


ABSTRACT: Our recent studies have demonstrated that the CD22 exon 12 deletion (CD22?E12) is a characteristic genetic defect of therapy-refractory clones in pediatric B-precursor acute lymphoblastic leukemia (BPL) and implicated the CD22?E12 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 CD22?E12 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 CD22?E12 genetic defect. We provide experimental evidence that the correction of the CD22?E12 genetic defect in human CD22?E12(+) 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 CD22?E12 product. The anti-leukemic activity of this RTM against BPL xenograft clones derived from CD22?E12(+) leukemia patients provides the preclinical proof-of-concept that correcting the CD22?E12 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.

SUBMITTER: Uckun FM 

PROVIDER: S-EPMC4373651 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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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.

Uckun Fatih M FM   Qazi Sanjive S   Ma Hong H   Reaman Gregory H GH   Mitchell Lloyd G LG  

Integrative biology : quantitative biosciences from nano to macro 20150201 2


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 corre  ...[more]

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