What is Chronic Myeloid Leukemia?
Chronic myeloid leukemia (CML) ranks third among all leukemia. It accounts for about 20% of cases of blood cancer. Currently, over 3 thousand patients are registered in Russia. The smallest of them is only 3 years old, the oldest is 90.
The incidence of CML is 1-1.5 cases per 100,000 population per year (15-20% of all cases of hemoblastosis in adults). Mostly middle-aged people get sick: the peak incidence rate falls on the age of 30-50 years, about 30% are patients older than 60 years. CML is rare in children, accounting for no more than 2-5% of the total number of leukemia. Men get sick more often than women (1: 1.5 ratio).
Causes of Chronic Myeloid Leukemia
Like the vast majority of other leukemia, chronic myeloid leukemia occurs as a result of acquired (i.e., non-congenital) damage to the chromosome apparatus of a single bone marrow stem cell.
The exact cause of this change in chromosomes in patients with CML is still unknown. Most likely, there is a random exchange of genetic material between chromosomes, which at a certain stage in the life of the cell are located in close proximity to each other.
The question of the influence on the incidence of CML by such factors as low doses of radiation, weak electromagnetic radiation, herbicides, insecticides, etc. remains an issue of significant increase in the incidence of CML in individuals exposed to ionizing radiation. Among chemical agents, the association with the onset of CML has been established only for benzene and mustard gas.
The substrate of chronic myelogenous leukemia is composed mainly of maturing and mature cells of the granulocyte series (metamyelocytes, stab and segmented granulocytes).
Pathogenesis during Chronic Myeloid Leukemia
It is believed that the translocation t (9; 22), leading to the formation of the BCR-ABL1 chimeric gene, plays a key role in the occurrence of chronic myeloid leukemia. Moreover, the 1st exon of the ABL1 gene is replaced by a different number of 5′-terminal exons of the BCR gene. Chimeric Bcr-Abl proteins (one of them is p210BCR-ABL1 protein) contain the N-terminal Bcr domains and the C-terminal Abl1 domains.
The ability of chimeric proteins to cause tumor transformation of normal hematopoietic stem cells has been demonstrated in vitro.
Oncogenicity of the p210BCR-ABL1 protein is also evidenced by experiments in mice that received a lethal dose of radiation. When they received bone marrow cells that were infected with a BCR-ABL1 gene-carrying retrovirus, half of the mice developed myeloproliferative syndrome, which resembled chronic myelogenous leukemia.
Other evidence for the role of the p210BCR-ABL1 protein in the development of chronic myelogenous leukemia follows from experiments with antisense oligonucleotides complementary to the transcript of the BCR-ABL1 gene. It was shown that these oligonucleotides inhibit the growth of colonies of tumor cells, while normal granulocyte and macrophage colonies continue to grow.
The fusion of the BCR gene with the ABL1 gene leads to an increase in the tyrosine kinase activity of the Abl1 protein, its ability to bind to DNA weakens, and binding to actin is enhanced.
At the same time, the detailed mechanism of the transformation of normal bone marrow cells into tumor cells is unknown.
The mechanism of the transition of the disease from the advanced stage to the blast crisis is also unclear. Fragility of chromosomes is inherent in a tumor clone: in addition to translocation t (9; 22), trisomy on the 8th chromosome, deletion in 17p can appear in tumor cells. The accumulation of mutations leads to a change in the properties of tumor cells. According to some researchers, the blast crisis development rate depends on the localization of the breakdown point of the BCR gene. Other researchers refute these data.
In a number of patients, blast crisis development is accompanied by various mutations of the TP53 gene and RB1 gene. Mutations of RAS genes are rare. There are few reports of the appearance in patients with chronic myelogenous leukemia of the protein p190BCR-ABL1 (it is often found in patients with acute lymphoblastic leukemia and sometimes in patients with acute myeloid leukemia), as well as mutations in the MYC gene.
Before the blast crisis, DNA methylation can occur at the BCR-ABL1 gene locus.
There is also information about the participation in the progression of chronic myeloid leukemia IL-1beta.
The data presented indicate that tumor progression is due to several mechanisms, but the exact role of each of them is unknown.