Future Approaches for Treating Chronic Myeloid Leukemia: CRISPR Therapy

Abstract

The constitutively active tyrosine-kinase BCR/ABL1 oncogene plays a key role in human chronic myeloid leukemia development and disease maintenance, and determines most of the features of this leukemia. For this reason, tyrosine-kinase inhibitors are the first-line treatment, offering most patients a life expectancy like that of an equivalent healthy person. However, since the oncogene stays intact, lifelong oral medication is essential, even though this triggers adverse effects in many patients. Furthermore, leukemic stem cells remain quiescent and resistance is observed in approximately 25% of patients. Thus, new therapeutic alternatives are still needed. In this scenario, the interruption/deletion of the oncogenic sequence might be an effective therapeutic option. The emergence of CRISPR (clustered regularly interspaced short palindromic repeats) technology can offer a definitive treatment based on its capacity to induce a specific DNA double strand break. Besides, it has the advantage of providing complete and permanent oncogene knockout, while tyrosine kinase inhibitors (TKIs) only ensure that BCR-ABL1 oncoprotein is inactivated during treatment. CRISPR/Cas9 cuts DNA in a sequence-specific manner making it possible to turn oncogenes off in a way that was not previously feasible in humans. This review describes chronic myeloid leukemia (CML) disease and the main advances in the genome-editing field by which it may be treated in the future.

From Descriptive to Functional Genomics of Leukemias Focusing on Genome Engineering Techniques

“…In 2020, Chia-Hwa Lee and his colleagues disrupted ABL1 in the human CML K562 cell line using a CRISPR/Cas9 lentiviral vector. They were able to show that disrupting BCR/ABL1 resulted in a lower rate of proliferation [ 78 ].…”

“…The first clinical trials involving CRISPR/Cas9 in humans were initiated in 2016 [ 78 , 123 ]. Researchers isolated immune cells from a patient’s blood and, using CRISPR/Cas9, disabled a gene in the cells.…”

The Progression of Chronic Myeloid Leukemia to Myeloid Sarcoma: A Systematic Review

“…Normal hematopoiesis is defined by the existence of hematopoietic stem cells capable of regulated selfrenewal and multipotency, resulting in balanced hematopoiesis between myeloid and lymphoid lineages [22]. The pathology of CML cases is attributed to myeloproliferative neoplasm, a rare blood cancer characterized by rapidly growing and unregulated myeloid cells [2,20].…”

Chronic myeloid leukemia stem cells: targeting therapeutic implications

“…Advances in molecular biology and genetics have expanded our knowledge of genes involved in disease development. In line with this, recently, the common techniques used to monitor CML patients, detect the Ph chromosome, and recognize the BCR-ABL1 transcript are conventional cytogenetics and fluorescence in situ hybridization (FISH), and reverse transcriptase-polymerase chain reaction (RT-PCR) [ 60 , 224 , 225 ]. RT-PCR is also used to assess the following molecular response to treatment, defined as the ratio of BCR-ABL1 to ABL1 transcripts (known as molecular response (MR)) and categories in different groups including complete cytogenetic remission (MR ≤ 1%), major molecular response (MMR) (MR ≤ 0.1%), deep molecular response (DMR) ( MR4 ≤ 0.01%), and molecularly undetectable leukemia MR4.5 ≤ 0.0032% [ 60 , 164 ].…”

“…In general, TKIs only inactivate the oncoprotein, but the oncogene continues unaffected and treatment discontinuation is only an option for a small subset of patients; therefore, the interruption/deletion of the oncogenic sequence might be an effective new therapeutic option [ 224 ]. The emergence of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technology can be a treatment based on its capacity to induce a specific DNA double-strand break in precise locations and providing complete and permanent oncogene knockout by generating an animal carrying highly targeted genetic modification [ 224 , 234 ]. Additionally, this system can be used to deliver combinations of guide RNAs to modify multiple genes in a single mouse hematopoietic stem cell, to more closely model the complexity of hematopoietic malignancy [ 235 ].…”