Introduction to chronic myeloid leukemia

Description: Chronic myelocytic leukemia (CML) is a hematopoietic stem cell clonal proliferative disease. The bone marrow is characterized by myeloid hyperplasia, peripheral blood leukocytosis and splenomegaly. Etiology: (1) The cause of the disease can increase the incidence of CML by ionizing radiation. The incidence of CML in survivors after the Hiroshima and long-term atomic bomb explosion, patients with ankylosing spondylitis receiving spinal radiotherapy, and cervical cancer patients receiving radiotherapy and other populations Compared to the apparent increase. Long-term exposure to benzene and various cancer patients undergoing chemotherapy can lead to CML, suggesting that certain chemicals are also involved in CML. The increased frequency of HLA antigens CW3 and CW4 in CML patients suggests that it may be a susceptibility gene for CML. Despite the reports of familial CML, CML familial aggregation is very rare, and there is no increase in the incidence of CML in other members of monozygotic twins. The parents and children of CML patients do not have CML-characterized Ph chromosomes, indicating that CML is an acquired Leukemia has nothing to do with genetic factors. (B) pathogenesis 1. Originated from hematopoietic stem cells CML is an acquired clonal disease originating from hematopoietic stem cells. The main evidences are: 1CML chronic phase may have red blood cells, neutrophils, acidophilic / basophils , monocytes and thrombocytosis; 2CML patients with erythroid cells, neutrophils, acidophilic / basophils, macrophages and megakaryocytes have Ph chromosome; 3 in G-6-PD heterozygous female CML In patients, red blood cells, neutrophils, acidophilic/basophils, monocytes, and platelets express the same G-6-PD isoenzyme, and fibroblasts or other somatic cells can detect two G types. -6-PD isoenzyme; 4 each cell analyzed has the same structural abnormality of chromosome 9 or 22; 5 molecular biology study chromosome 22 breakpoint variation exists only in different CML patients, but in the same patient The breakpoints in the cells were consistent; 6 X-linked locus polymorphism and inactivation pattern analysis also confirmed that CML is monoclonal hematopoiesis. 2. Abnormal progenitor cells have obvious cell dynamics abnormalities in the mature myeloid progenitor cells, with low cleavage index, few cells in the DNA synthesis phase, prolonged cell cycle, unbalanced nucleoplasm development, and mature granulocyte half-life is normal. Granulocyte elongation. The 3H suicide test confirmed that only 20% of CML colonies were in the DNA synthesis stage, while normal humans were 40%. The CML primary and promyelocytic labeling index was lower than that of normal people, while the middle and late myelocyte marker index was normal. There is no significant difference compared to the photo. Hematopoietic progenitor colony culture showed that the proliferation ability of CML myeloid progenitor cells and peripheral blood progenitor cells was different. The number of CFU-GM and BFU-E in bone marrow was usually higher than that of normal controls, but it could be normal or decreased, while peripheral blood could be elevated. Up to 100 times the normal control. Long-term culture of bone marrow cells in Ph-positive CML patients revealed that Ph-negative progenitor cells were detected in the culture medium after several weeks of culture, which has been confirmed to be mainly due to abnormal adhesion of CML hematopoietic progenitor cells. 3. Molecular Pathology In 1960, Nowell and Hungerfor described the CML-associated Ph chromosome, which was the first non-random chromosomal abnormality associated with a specific human tumor. In 1973, Rowley used quinine and Giemsa staining techniques to demonstrate for the first time that the Ph chromosome (22q-abnormal) found in CML was caused by t(9;22)(q34;q11) chromosomal translocation. The ABL gene was cloned in the 9q34 break region in 1982. In 1983, it was confirmed that the gene fragment located in q34 translocated to chromosome 22 and a gene called BCR in the 22q11 fragmentation region formed a BCR-ABL fusion gene. (1) ABL gene: The proto-oncogene c-abl is located at q34 and is highly conserved during species development. It encodes a protein that is ubiquitously expressed in all mammalian tissues and various cell types. The c-abl is about 230 kb long. Containing 11 exons, the trend is from the 5' end to the centromere. The first exon of this gene has two forms, exons 1a and 1b, and thus there are two different c-abl mRNAs. The first one is called 1a-11 and is 6 kb long, including exons 1a-11. The other, called 1b, starts from exon 1b, spans exon 1a and the first intron, and is adjacent to exon 2-11, and is 6 kb in length. RNA transcription coding of these two ABLs Two different ABL proteins with a molecular weight of 145,000. DNA sequence analysis found. C-abl is a non-receptor protein-tyrosine kinase family. In addition to the kinase fragment, this gene also has SH2 and SH3 fragments that are important in the interaction and regulation of signaling proteins. C-abl is characterized by a A large C-terminal non-catalytic fragment containing an important sequence of DNA and cytoskeleton binding and a region involved in the signal. Normal p145ABL shuttles between the nucleus and the cytosol, mainly localized to the nucleus, and has a low tyrosine kinase activity. The activity and intracellular localization of p145ABL are regulated by integrins of the cytoskeleton and extracellular matrix. Existing studies have shown that at least in fibroblasts, ABL activation requires cell adhesion, so ABL may transmit integrin signaling to the nucleus. Thus acting as a bridge between adhesion and cell cycle signals, involved in cell growth and differentiation control. (2) BCR gene: The BCR gene is located at 22q11, 130 kb in length, with 21 exons, starting from the 5' end to the central granule. There are two different BCR mRNA transcription patterns of 4.5 kb and 6.7 kb, encoding a protein p160 BCR with a molecular weight of 160,000, which has kinase activity. The C-terminus of p160 BCR is associated with the GTP activity of the ras-associated GTP-binding protein p21. (3) BCR-ABL gene: The c-abl gene located at 9q34 is located on chromosome 22 and the bcr gene located at 22q11 forms a BCR-ABL fusion gene. So far, three bcr breakpoint clusters have been found in CML patients, which are M-bcr, m-bcr, u-bcl and 6 BCR-ABL fusion transcription modes, and b2a2, b3a2, b2a3 corresponding to M-bcr. The encoded protein is p210, corresponding to m-bcr, there is ela2, the encoded protein is p190, and corresponding to u-bcr, there is e19a2, and the encoded protein is p230. BCR-ABL has been shown to cause CML in mouse models in vivo. The BCR-ABL fusion protein is localized in the cytoplasm and has extremely high tyrosine kinase activity by altering some of the key regulatory proteins of the BCR-ABL catalytic substrate. The status of activation activates a variety of signaling pathways, such as by activating the Ras signaling pathway involved in cell proliferation and differentiation, increasing the number of progenitor cells, reducing the number of stem cells, and making stem cells part of the proliferation pool, thereby allowing immature granulocytes to expand. Another mechanism of BCR-ABL action is to alter normal integrin function. Normal hematopoietic progenitor cells adhere to the extracellular matrix, and adhesion is mediated by progenitor cell surface receptors, especially integrins. BCR-ABL interferes with β1. The function of integrins leads to defects in the cell adhesion function of CML cells, thereby releasing immature cells to the peripheral blood and migrating to the extramedullary space. Recently, the pathogenesis of CML has progressed: 1 In vitro culture, BCR-ABL prolongs the factor-independent growth time of CML progenitor cells by inhibiting apoptosis; 2 After down-regulating BCR-ABL expression by antisense oligonucleotides It is possible to inhibit the growth of leukemia cells in mice by increasing the sensitivity of cells to apoptosis, especially to reduce the formation of early progenitor cells in CML patients and reduce the cell proliferation of CML-like cell lines; 3 expressing BCR-ABL, transformed, Factor-independent, tumorigenic mouse hematopoietic cells increase sensitivity to apoptosis by upregulating bcl-2. When bcl-2 expression is inhibited, BCR-ABL positive cells become factor-dependent and Non-tumorigenic. The above experimental results indicate that BCR-ABL inhibits apoptosis and leads to the continuous expansion of myeloid cells, which is another pathogenesis of CML. (4) Mechanism of catastrophic changes: Cytogenetic studies have found that 80% of patients with AP or BP CML have secondary chromosomal abnormalities. The most common abnormalities are +8, +Ph, i(17), +19, +21 and -Y. About 80% of patients with acute myeloid leukemia (acute granulosis) have non-random sex chromosomal abnormalities, and their karyotype often appears as hyperdiploid, the most common abnormality is +8, and +8 often with other chromosomes Abnormalities such as i(17), +Ph, and +19 occur simultaneously, followed by +Ph, i(17), and -Y. About 30% of patients with acute lymphoblastic leukemia (acute lymphocytosis) have secondary clonal chromosomal abnormalities, often chromosome loss, which is characterized by subdiploid or structural abnormalities. Common abnormalities are +Ph and -Y, + 8 rare, i (17) has not been reported, -7, 14q + and acute lymphoblastic specific. Although studies have found that CML has a mutation in N-Ras gene and an increase in c-Myc gene expression in blast crisis, its incidence is extremely low. The Rb gene is rarely altered in patients with blast crisis. Sill et al. found that the homozygous deletion of the p161NK4A gene is associated with CML acute leaching. The most important molecular mechanism of CML is the p53 gene. 20% to 30% of patients with acute granulosis have abnormalities in p53 gene structure and expression. The characteristics of CMLp53 gene change are: 1 major changes are gene rearrangement and mutation; 2 mainly seen in acute granules, acute leaching is rare; 3p53 mutations are common in patients with 17P-abnormalities; 4p53 mutations can lead to acute granulocyte changes in CML. Recently, there have been reports on the relationship between the degree of methylation of the calmodulin gene, the change of telomere length and telomerase activity and the rapid change of CML, but its significance needs to be further clarified. Symptoms: 1. Chronic phase (1) Symptoms: Most CML patients are usually clinically “chronic” or “stable”, which lasts for 3 to 4 years. Common symptoms include: anemia, spleen discomfort, bleeding and fatigue, weight loss and low fever. 20% to 40% of patients are asymptomatic, diagnosed by routine physical examination of white blood cell count, increased platelet count, or enlarged spleen. A small number of patients have gout joint pain. In addition, there are visual impairments, neurological diseases, and abnormal penile erections. Patients in the chronic phase are less susceptible to infection and fever is rare. (2) Signs: mainly manifested as organ infiltration. 90% of patients have splenomegaly, varying degrees, and the spleen can reach the spleen and the spleen extends to the pelvic cavity. When the spleen is embolized, the spleen area may touch the friction or smell the friction sound. There may be mild to moderate hepatic enlargement, and lymphadenopathy is rare. The sternum often has tenderness, with the lower end of the sternum stem. Retinal infiltration of the fundus, visible retinal vasospasm dilatation, and visible flaky hemorrhage and white infiltration center. 2. After a few months or years in the blast phase of chronic phase, malignant hematopoietic stem cells are extremely proliferated. Bone marrow granules + promyelocytic cells ≥20% may be associated with changes in myelofibrosis caused by excessive platelet-derived growth factor. It is not predictable when each patient will change rapidly. In the event of a sudden change, the condition deteriorates rapidly and the treatment is very difficult. The survival period rarely exceeds 6 to 12 months. (1) Symptoms: fever of unknown cause, further enlargement of spleen; infiltration of bone pain, hemorrhage and extramedullary mass, such as lymphadenopathy, soft tissue mass or osteolytic lesions. (2) Rapid change type: 1 about 65% for acute granulation: including: A. primordial granulocyte crisis, sudden sudden changes in the disease, a large number of granulocytes in the bone marrow or blood, primary particles + early granules > 90% The disease develops rapidly, the course of disease is short, and it usually dies within 1 to 2 months. B. Slow-granular blast, which refers to the conversion process of CML over several weeks to several months, and all signs of acute leukemia appear. The original + early juvenile in the bone marrow is >20%. Resistant to treatment, the survival period is no more than 6 months. 2 about 30% for acute lymphoblastic: including common acute lymphoblastic leukemia (C-ALL), non-T non-B lymphocytic leukemia, pre-B-cell leukemia and B, T-cell leukemia. Acute diarrhea can be temporarily relieved by vincristine and prednisone, but eventually died within 0.5 to 1 year. 35% are other rare types of acute myeloid changes: including tissue cell changes, erythroleukemia, megakaryocyte changes, and acute monocyte changes. Changes in blood, bone marrow, and cell morphology have their corresponding characteristics, and the prognosis is poor. Most patients die within 6 months after the sudden change. 3. The acceleration period is between the chronic phase and the acute phase. In this period, the phenomenon of hypothermia and splenomegaly begins to appear in the clinic. The anemia gradually increases, the white blood cells continue to rise, the immature cells begin to increase, and the original granules + early granules ≥10%. The original effective drug appeared to be resistant. It can evolve into a typical acute phase in weeks or months. Chromosomes have changed in this phase, such as the acute phase, so chromosome changes are earlier than hematological and clinical changes, and can be used as indicators of disease progression and prognosis. The typical CML is accompanied by splenomegaly, and the number of white blood cells in the peripheral blood is increased. It can be seen that immature granulocytes, eosinophils and basophils are increased in each stage. Myeloid hyperplasia is marked or extremely active, mainly granulocyte cell proliferation, moderately young and rod-shaped granulocytes are proliferated, eosinophils and/or basophils are also increased, and megakaryocyte cell lines often proliferate. Neutrophil alkaline phosphatase score (ALP) is reduced. Cytogenetic examination of Ph chromosome or application of molecular biology methods to detect BCR-ABL gene rearrangement or fusion, diagnosis is not difficult. Diagnostic criteria: Typical CML, also known as chronic myeloid leukemia (CGL), must be positive for the Ph chromosome-positive BCR-ABL fusion gene, or negative for the Ph chromosome, but positive for the BCR-ABL fusion gene. At the same time, there must be one of the following two: 1 peripheral blood leukocytes increased, mainly neutrophils, immature granulocytes > 10%, primordial cells (I + II type) < 10%. 2 Myeloid hyperplasia was marked to be extremely active, with neutral neutrophils and neutrophils in the following stages, and the original cells (I+II type) <10%. 1. Staging criteria Because 90% of CML has a moderate period of about 3 years after the chronic phase, it will inevitably enter the accelerated phase, and finally develop to the blast phase, ending with acute leukocyte disease, so it is necessary to understand the characteristics of each period. The following describes the staging standards currently applied in China. (1) Chronic phase: 1 clinical manifestations: asymptomatic, or only low fever, fatigue, excessive sweating, weight loss and other symptoms. 2 blood: white blood cell count is increased, mainly neutral, young, young, rod and granulocyte, primordial cells (I + II type) <10%, alkalophilic and eosinophilia, may have a small amount of childish Red blood cells. 3 bone marrow: hyperplasia is extremely active, mainly granulocyte hyperplasia. Middle, young and granulocytes increased, and the original cells (type I+II) <10%. The 4Ph chromosome and/or BCR-ABL fusion gene is positive. 5 Peripheral blood CFU-GM culture: the number of colonies and clusters was significantly higher than normal. (2) If the acceleration period has any of the following 2 items, it can be diagnosed. Read more...