Журнал гематологии и тромбоэмболических заболеваний
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ISSN: 2329-8790
ISSN: 2329-8790
Ana Luisa Miranda-Vilela and Graciana Souza Lordelo
Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm derived from an abnormal pluripotent hematopoietic stem cell that underwent a chromosomal translocation t(9;22)(q34;q11) acquiring the BCR-ABL1 fusion gene, also known as the Philadelphia chromosome. Although the clinical and biological aspects are well documented, little is known about individual susceptibility to CML. There are no known hereditary, familial, geographic, ethnic, or economic associations with CML, and the mechanisms behind disease progression are not fully understood. However, while a specific chromosomal translocation is the common oncogenetic mechanism of CML, it may have environmental causes such as irradiation and chemical (e.g., benzene) exposure, which exert toxicity via pro-oxidant mechanisms. Oxidative stress has been observed in several hematopoietic malignancies, including acute and chronic myeloid leukemias. It is known that BCR/ABL expression stimulates reactive oxygen species (ROS) production in hematopoietic progenitor cells, and studies have suggested that ROS may contribute to increased DNA damage in CML cells. Leukemia cell lines expressing BCR-ABL1 kinase accumulate ROS and oxidative DNA damage, resulting in genomic instability, which leads to the disease relapse and/or malignant progression to a fatal blast phase. These suggest a probable genetic susceptibility to this disease related to the body’s ability to defend itself from external aggression such as chemicals, ionizing radiation and others, through functional polymorphic variant enzymes that metabolize toxicants and/or protect against oxidative stress. Thus, this review aims to address a comprehensive summary of CML, including the physiological function of the normal proteins encoded by the ABL1 and BCR genes and the oncogenetic mechanism of the BCR-ABL1 fusion proteins, as well as to discuss the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR), glutathione S-transferases (GSTs M1 and T1) and haptoglobin (Hp) genes in the susceptibility to Chronic Myeloid Leukemia (CML).