Purging of chronic myelogenous leukemia cells by retrovirally expressed anti-bcr-abl ribozymes with specific cellular compartmentalization

Cancer Gene Therapy
Ramiro Mendoza-MaldonadoMauro Giacca

Abstract

In patients with chronic myelogenous leukemia (CML), abnormal expansion of myeloid cells is maintained by expression of the p210(bcr-abl) fusion protein. Thus, this protein and its mRNA represent primary targets to inhibit proliferation of these cells. Here we describe the properties of a ribozyme against the bcr-abl mRNA, expressed as a fusion transcript with the human U1 small nuclear RNA or the adenovirus VA1 RNA and delivered to the cells through retroviral vectors. These fusion ribozymes are specifically localized in the nucleus or in the cytoplasm, respectively. Transduction of 32D-LG7 myeloid cells, whose growth is IL-3 independent thanks to deregulated bcr-abl expression, imposed strong negative selective pressure on cell growth and induced restoration of an IL-3-dependent phenotype. Although expressed at a level similar to that of the U1-fusion ribozyme, the cytoplasmic VA1 ribozyme was a more powerful inhibitor of p210(bcr-abl) gene expression. In cells transduced with the vector expressing this ribozyme, the levels of the bcr-abl transcript were reduced up to 10(4)-fold, the p210(bcr-abl) protein became undetectable, and the cells underwent massive apoptosis when cultured in the absence of IL-3. Transduction of prima...Continue Reading

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Citations

Jan 26, 2013·Biotechnology Advances·Virendra Gajbhiye, Shaoqin Gong
Oct 15, 2003·Clinical Lymphoma·Tommy AlainAnna E Kossakowska
May 18, 2004·Biochemical and Biophysical Research Communications·Jin-Hwang LiuPo-Min Chen
Mar 12, 2021·Current Oncology·Vanessa InnaoAlessandro Allegra

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