Please use this identifier to cite or link to this item:
|Title:||CRISPR-Cas9 Technology as a Tool to Target Gene Drivers in Cancer: Proof of Concept and New Opportunities to Treat Chronic Myeloid Leukemia.|
Cell Line, Tumor
Disease Models, Animal
Fusion Proteins, bcr-abl
Gene Transfer Techniques
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplastic Stem Cells
Proof of Concept Study
|Abstract:||Chronic myeloid leukemia (CML) is a hematopoietic malignancy produced by a unique oncogenic event involving the constitutively active tyrosine-kinase (TK) BCR/ABL1. TK inhibitors (TKI) changed its prognosis and natural history. Unfortunately, ABL1 remains unaffected by TKIs. Leukemic stem cells (LSCs) remain, and resistant mutations arise during treatment. To address this problem, we have designed a therapeutic CRISPR-Cas9 deletion system targeting BCR/ABL1. The system was efficiently electroporated to cell lines, LSCs from a CML murine model, and LSCs from CML patients at diagnosis, generating a specific ABL1 null mutation at high efficiency and allowing the edited leukemic cells to be detected and tracked. The CRISPR-Cas9 deletion system triggered cell proliferation arrest and apoptosis in murine and human CML cell lines. Patient and murine-derived xenografts with CRISPR-edited LSCs in NOD SCID gamma niches revealed that normal multipotency and repopulation ability of CRISPR edited LSCs were fully restored. Normal hematopoiesis was restored, avoiding myeloid bias. To the best of our knowledge, we show for the first time how a CRISPR-Cas9 deletion system efficiently interrupts BCR/ABL1 oncogene in primary LSCs to bestow a therapeutic benefit. This study is a proof of concept for genome editing in all those diseases, like CML, sustained by a single oncogenic event, opening up new therapeutic opportunities.|
|Appears in Collections:||Fundaciones e Institutos de Investigación > FIB H. Infantil U. Niño Jesús > Artículos|
Files in This Item:
The file with the full text of this item is not available due to copyright restrictions or because there is no digital version. Authors can contact the head of the repository of their center to incorporate the corresponding file.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.