THE IMPORTANCE OF MICRORNAS IN CHRONIC MYELOID LEUKEMIA

Independently of each other, Rudolf Virchow and John Bennett in 1845, diagnosed similar symptoms of leukemia in different patients. Furthermore, the term "leukemia" was first used by Rudolf Virchow. Leukemia is a type of cancer in which blood cells proliferate uncontrollably as a result of alterations in hematopoietic stem cells. Chronic Myeloid Leukemia (CML) was clarified by John Bennett and Rudolf Virchow, after the definition of leukemia in 1845, independently of each other. The incidence of CML among all adult leukemia cases is 15-20%. The annual new case incidence is 1-2 in 100, 000 people. While usually diagnosed in patients 65 years and older, it is also observed in patients under 65 years and rarely in children. Although it is a disease seen in both sexes, the incidence rate in men (2. 2 per 100, 000 people) is higher than that in women (1. 4 per 100, 000 people). CML is a slowly progressive myeloproliferative disease in the group of rare diseases. Caused by genetic abnormalities in hematopoietic stem cells, which cause myeloid cells to proliferate uncontrollably at different maturation stages and accumulate in the bone marrow and peripheral circulation. CML is characterized by myeloid hyperplasia, a rise in granulocyte-derived leukocytes, splenomegaly, and the presence of the Philadelphia Chromosome (Ph). The phases of CML consisting of 3 stages are shown in Figure 3. The chronic phase, in which myeloid hyperplasia with Philadelphia Chromosomes is observed, is usually the stage in which patients are diagnosed. The accelerated phase is characterized by an increase in the rate of myeloid cell proliferation and the appearance of additional mutations. When the number of mutant myeloid cells grows out of control, different genetic alterations might occur. In the blastic phase, the growth of blast cells surpasses a particular threshold, causing blastic crisis and can usually result in the conversion of chronic leukemia to acute leukemia. CML patients usually have no symptoms, and it is discovered by a blood test or through complaints related to the formation of splenomegaly. Cytogenetic tests, the fluorescence in situ hybridization (FISH) method to determine the Ph chromosome, or molecular methods are used in the diagnosis of the disease. It is identified that the Philadelphia chromosome is present in the genetic test results of 90-95% of the patients in the chronic phase stage. The Philadelphia Chromosome was discovered (in 1960) in a study by Peter Nowell and David Hungerford. In 1973, Janet Rowley demonstrated that the Philadelphia Chromosome (Ph) was formed as a result of translocation of the q34 region of the 9th chromosome with the q11 region of the 22nd chromosome, as shown in Figure 2. As a result of this translocation of chromosomes, the BCR gene on the 22nd chromosome and the ABL1 proto-oncogenes on the 9th chromosome fuse to form the BCR/ABL1 oncogene. The product of the BCR/ABL1 fusion is the oncoprotein p210 (molecular weight is 210 kDa). This oncoprotein causes the transformation of hematopoietic stem cells by affecting tyrosine kinase activity. As a result of this change, research has shown that myeloid cells are succeeded to avoid apoptosis and are proceeded to proliferate uncontrollably. Although the p210 protein is the most common product of the BCR/ABL1 gene, investigations reveal that different products (p190, e14a3, e13a3, e1a3, e19a3, e6a2, e8a2, and e18a2) occur depending on the chromosome breakpoints and junctions. In CML patients at first times, cytotoxic therapies (arsenic, hydroxyurea, busulfan, etc. ) were used to diminish the increasing number of cells, but interferon-a was utilized to achieve cytogenetic remission at later years. Allogeneic stem cell transplantation was the first favored approach to assure long-term survival for patients in the chronic phase in the 1990s, due to the substantial adverse effects of the medications utilized. New methods and medications have been improved in diagnosing and treatment of CML since the description of the BCR/ABL1 gene. The most notable of these treatments is treatment with imatinib molecules, which improved in the 2000s. Imatinib is the first therapy option for CML patients in the chronic phase nowadays, and allogeneic stem cell transplantation is utilized for patients who cannot be treated with medicines. Figure 3 depicts the basic mechanism of the imatinib molecule, which operates as a BCR/ABL tyrosine kinase inhibitor (TKI). TKI interacts with the BCR/ABL tyrosine kinase's ATP binding site, preventing it and suppressing protein kinase phosphorylation. As a result, the activation of the protein that is the BCR/ABL substrate is blocked. Over time, tyrosine kinase inhibitors like dasatinib, nilotinib, and bosutinib (derivatives of imatinib), which have stronger biochemical interactions than imatinib, have been produced. Other medications with derivatives are employed if the intended outcome cannot be attained after using the imatinib molecule or if the drug's impact changes with time. Different drug derivatives and daily intake are determined in patients receiving TKI treatment, based on the patient's genetic background and the medicine's action over time. As a result, the mechanism that causes CML to arise in patients should be thoroughly understood. In Chronic Myeloid Leukemia patients, thanks to TKI treatment and the latest technologies, it has been possible for the patients to continue their lives in a high-quality manner and the survival rate (it reached 90-95%) has increased. However, various issues can arise when using TKI therapy. The medicine's impact may fade over time in some patients, the treatment may cause side effects, and the use of imatinib and its derivatives during pregnancy may harm the embryo. Because TKI treatment does not target mutant myeloid stem cells, a durable outcome cannot be obtained. As a result, patients may be required to take imatinib or its variants for the rest of their lives, and the high expense of medication production adds to the problem. All these problems have led scientists to seek to better understand the mechanism of CML formation, investigate the mechanisms that cause drug resistance, and develop permanent treatment methods. TFR (treatment-free remission) is a non-drug therapeutic option. The purpose of this method is to terminate TKI treatment and stop using the drug in patients whose disease symptoms completely disappear after a certain period of use of imatinib or other drugs its derivatives.