CRISPR/Cas9 technology abolishes the BCR/ABL1 oncogene effect in chronic myeloid leukemia and restores normal hematopoiesis

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease produced by a unique oncogenic event involving the constitutively active tyrosine kinase (TK) BCR-ABL1. TK activity explains most features of CML, such as tumor development and maintenance. TK-inhibitory (TKI) drugs have changed its prognosis and natural history. Unfortunately, since ABL1 gene remains unaffected by TKIs, most patients should be treated with lifelong oral medication, resistant mutations arise and adverse effects occur during treatment in almost 25% of patients To address this problem, we have designed a potentially definitive therapeutic alternative with CRISPR/Cas9 genome editing nucleases that target leukemic stem cells (LSCs). CRISPR-edited LSCs lose their tumorigenic capacity and restore their own multipotency. The strategy was evaluated for the first time in a CML mouse model and in orthotopic assays with primary LSCs from CML patients. In Both systems, CRISPR-edited LSCs repopulated and restored the normal hematopoiesis in immunodeficient NSG niches providing a significant therapeutic benefit. We show for the first time how CRISPR technology permanently interrupts and avoids the BCR/ABL1 oncogene expression in human and mouse LSCs suggesting that human CML is an ideal candidate for CRISPR therapy, and providing proof-of-principle for genome editing in CML patients.