Abstract
Knowledge on acute myeloid leukemia pathogenesis and treatment has progressed recently, but not enough to provide ideal management. Improving the prognosis of acute myeloid leukemia patients depends on advances in molecular biology for the detection of new therapeutic targets and the production of effective drugs. The CRISPR/Cas9 technology allows gene insertions and deletions and it is the first step in investigating the function of their encoded proteins. Thus, new experimental models have been developed and progress has been made in understanding protein metabolism, antitumor activity, leukemic cell maintenance, differentiation, growth, apoptosis, and self-renewal, the combined pathogenetic mechanisms involved in leukemogenesis. The CRISPR/Cas9 system is used to understand drug resistance and find solutions to overcome it. The therapeutic progress achieved using the CRISPR/Cas9 system is remarkable. FST gene removal inhibited acute myeloid leukemia cell growth. Lysine acetyltransferase gene deletion contributed to decreased proliferation rate, increased apoptosis, and favored differentiation of acute myelid leukemia cells carrying MLL-X gene fusions. The removal of CD38 gene from NK cells decreased NK fratricidal cells contributing to increased efficacy of new CD38 CAR-NK cells to target leukemic blasts. BCL2 knockout has synergistic effects with FLT3 inhibitors. Exportin 1 knockout is synergistic with midostaurin treatment in acute myeloid leukemia with FLT3-ITD mutation. Using the results of CRISPR/Cas9 libraries and technology application will allow us to get closer to achieving the goal of curing acute myeloid leukemia in the coming decades.
Highlights
Acute myeloid leukemia (AML) is an aggressive malignant hemopathy
Knockdown of genes encoding mTORC1 components obtained using Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas[9] technology, or concomitant pharmacological inhibition of mTORC1 and Lysine-specific demethylase 1 (LSD1) leads to a higher cell differentiation both in vitro and in vivo
Progress in understanding the pathogenesis of AML is dependent on advanced methods of molecular biology
Summary
Acute myeloid leukemia (AML) is an aggressive malignant hemopathy. Its prognosis continues to be poor with the current standard of care, as in many patients, the disease relapses or becomes refractory[1]. The small nucleotide insertions or deletions obtained using the CRISPR-Cas[9] technique do not always produce a nonfunctional gene, but one that encodes a functionally active protein. CRISPR/Cas[9] libraries were used to identify effector genes whose role was not known in AML These AMLrelated genes are involved in various cellular pathogenetic mechanisms, such as signaling transduction, energy metabolism, transcriptional regulation, and epigenetics. Oncogenesis is the result of somatic mutations that occur sequentially and produce successive clonal populations Such a clonal evolution model of AML was obtained using induced pluripotent stem cells (iPSC) and CRISPR/Cas[9] technology.
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