Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics
Jami McLaughlin1, Donghui Cheng, Oded Singer
1Department of Microbiology, Immunology, and Molecular Genetics and Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095, USA.
Abstract:
Many cancers and leukemias are associated with strong dominant oncogenic mutations that activate tyrosine kinases and other classes of molecules, including transcription factors and antiapoptotic mechanisms. Some of these events can be targeted with small molecules or antibody-based therapeutics, but many remain intractable. In addition, cancer-related enzyme targets can often mutate, and drug-resistant variants are selected. Therapies directed at the mRNA encoding dominant oncogenes could provide a more global set of technologies for cancer treatment. To test this concept, we have used the model of transformation of hematopoietic cells by the chimeric Bcr-Abl oncogene, a highly activated tyrosine kinase. Our results show that tandem arrays of miRNA mimics, but not single miRNA mimics, directed against the Abl portion of the mRNA and introduced by lentiviral vectors can effectively alter the leukemogenic potency when the degree of suppression of expression of Bcr-Abl is reduced >200-fold from control levels. Only methods capable of such dramatic sustained reduction in the level of expression of highly activated kinase oncogenes are likely to be effective in controlling malignant cell populations.
Insights
Targeting cancer-causing mRNA with multiple microRNA mimics can significantly reduce leukemic cell potency. This approach shows promise for treating cancers with highly activated tyrosine kinases, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Many cancers involve oncogenic mutations activating tyrosine kinases, transcription factors, and antiapoptotic mechanisms.
- Current targeted therapies face challenges due to target mutation and drug resistance.
- Targeting mRNA offers a potential global strategy for cancer treatment.
Purpose of the Study:
- To investigate the efficacy of targeting oncogenic mRNA using microRNA (miRNA) mimics.
- To evaluate the potential of miRNA mimics in treating hematopoietic cell transformation driven by the Bcr-Abl oncogene.
Main Methods:
- Utilized lentiviral vectors to deliver tandem arrays of miRNA mimics targeting the Abl portion of the Bcr-Abl mRNA.
- Employed a model of hematopoietic cell transformation by the chimeric Bcr-Abl oncogene.
- Assessed the reduction in Bcr-Abl expression and its impact on leukemogenic potency.
Main Results:
- Tandem arrays of miRNA mimics, but not single mimics, significantly reduced Bcr-Abl expression (>200-fold).
- This dramatic suppression of Bcr-Abl effectively altered the leukemogenic potency of transformed cells.
- Sustained, significant reduction in oncogene expression is crucial for controlling malignant cell populations.
Conclusions:
- Targeting oncogenic mRNA with tandem miRNA mimics is a viable strategy for cancer therapy.
- Highly potent and sustained suppression of activated kinase oncogenes is necessary for effective cancer treatment.
- This approach holds promise for overcoming drug resistance in certain cancers.
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