Chronic myelogenous leukemia

Introduction to chronic myeloid leukemia Chronic myeloid leukemia is a myeloproliferative disorder characterized by excessive production of granulocytes, including granulocytes in mature and naive stages. In the early stages of the disease, these cells still have the ability to differentiate and the bone marrow function is normal. The disease often remains stable for several years, and finally becomes a disease with a higher degree of malignancy. The patients are mostly between the ages of 30 and 40, and those under the age of 20 are rare. basic knowledge The proportion of illness: 0.006% Susceptible people: no specific people Mode of infection: non-infectious Complications: edema, fundus hemorrhage

Causes of chronic myeloid leukemia

(1) Causes of the disease

Ionizing radiation (25%):

Ionizing radiation can increase the incidence of CML. The incidence of CML in survivors after Hiroshima and long-term atomic bombing, in patients with ankylosing spondylitis undergoing spinal radiotherapy, and cervical cancer receiving radiotherapy is significantly higher than in other populations.

Prolonged exposure to benzene or chemotherapy (20%):

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.

Other (5%):

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.

(two) 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.

The erythroid cells, neutrophils, acidophilic/basophils, macrophages, and megakaryocytes of 2CML patients all have Ph chromosomes.

3 In G-6-PD heterozygous female CML patients, red blood cells, neutrophils, acidophilic/basophils, monocytes and platelets express the same G-6-PD isoenzyme, fibroblasts. Or two somatic cells can detect two G-6-PD isozymes.

4 Each of the analyzed cells had identical structural abnormalities on chromosome 9 or 22.

5 Molecular biology studies The chromosome 22 breakpoint variation exists only in different CML patients, and the breakpoints are consistent in different cells of the same patient.

6 X-linked gene locus polymorphism and inactivation pattern analysis also confirmed that CML is monoclonal hematopoiesis.

2. Abnormal function of progenitor cells: Relatively mature myeloid progenitor cells have obvious cell dynamic abnormalities, low fission index, few cells in DNA synthesis phase, prolonged cell cycle, unbalanced nucleoplasm development, and mature granulocyte half-life ratio 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, 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 has a length of 6 kb. A variety of 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 of 160,000 protein p160 BCR, 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. The BCR-ABL fusion protein is localized in the cytoplasm and has a very 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 1. 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, research on the pathogenesis of CML has progressed: 1 In vitro culture found that BCR-ABL prolongs the factor-independent growth time of CML progenitor cells by inhibiting apoptosis. 2 Down-regulation of BCR-ABL expression by antisense oligonucleotide may inhibit the growth of leukemia cells in mice by increasing the sensitivity of cells to apoptosis, especially reducing the formation of early progenitor colonies in CML patients and reducing CML-like cell lines. Cell proliferation. 3 BCR-ABL, transformed, factor-independent, tumorigenic mouse hematopoietic cells increase sensitivity to apoptosis by up-regulating bcl-2. When bcl-2 expression is suppressed, 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 The main changes are gene rearrangement and mutation. 2 mainly seen in acute granulation, acute leaching is extremely rare. 3p53 mutations are common in patients with 17P-abnormalities. 4p53 mutations can cause 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.

Chronic myelogenous leukemia prevention

Slow-grain patient diet should follow 6 should 7 bogey

should

(1) Hepatosplenomegaly should eat red bean, plum, jujube, wakame, turtle, turtle, kelp, seaweed.

(2) Bleeding should eat sputum, grapes, leeks, mushrooms, mushrooms, fungus, day lily, cat meat, squid.

(3) Anemia should be eaten pig liver, yellow croaker, sea cucumber, squid, squid, citron, sesame, bee milk.

(4) It is advisable to eat more foods with anti-leukemia effects: alfalfa, alfalfa, garlic, wheat, carrots, walnuts, dandelions, oysters.

(5) fever should eat cardamom, scallion, winter vegetables, leeks, plum, ginkgo, mung bean, bitter gourd, Ling, zucchini, jellyfish, squid, pig spinal cord.

(6) swollen lymph nodes should eat glutinous, chestnut, mulberry, walnut, lychee, medlar, stingray, cat meat, sheep belly, medlar, clam, oyster, turtle, turtle.

avoid

(1) Avoid excitatory beverages such as coffee and strong tea.

(2) Avoid warm food such as lamb, dog meat, leeks, and pepper.

(3) Avoid cock, pork noodles and other hair.

(4) Avoid pig's feet, chicken internal organs and head and feet, crabs, squid, squid, etc.

(5) Avoid tobacco and alcohol.

(6) Avoid stimulating food such as onion, garlic, ginger and cinnamon.

(7) Avoid fatty, fried, mildew, pickled food.

Chronic myeloid leukemia complications Complications, edema, fundus hemorrhage

When the white blood cell count is >100×10 ⁹ /L, there may be leukocyte stasis syndrome, dyspnea, purpura, organ infarction, fundus vein dilatation, optic nerve head edema, fundus hemorrhage, nerve changes and even central nervous system hemorrhage. Giant spleen can be associated with spleen infarction.

Chronic myeloid leukemia symptoms Common symptoms Fatigue fever edema Joint pain maculopapular coffee spot liver splenomegaly Liver enlargement Eczema lymphadenopathy

Chronic leukemia is less in childhood, accounting for 3% to 5% of childhood leukemia, mainly chronic myelogenors leukemia (CML).

The clinical manifestations of CML in infants are significantly different from those of adult CML. Therefore, pediatric CML is generally divided into juvenile and adult types. The literature also includes infants, families, infants, and adults. The type is similar to the infant type, but it is often found in close relatives.

Juvenile chronic myeloid leukemia

This type occurs almost exclusively in children under 5 years of age, especially in infants under 2 years of age. Males have more outbreaks than women, and can occur in familial neurofibromas, genitourinary malformations or mental retardation.

Onset can be urgent or slow, often with respiratory symptoms as the main complaint, more common facial rash or eczema-like rash, even purulent rash, also visible skin coffee spots, skin symptoms can appear in the months before leukemia cell infiltration, lymphadenopathy Large, even purulent, progressive hepatosplenomegaly, it is not uncommon to send blood due to thrombocytopenia.

JCML originates from pluripotent hematopoietic stem cells, so it can cause erythroid hyperplasia, abnormal platelet count and quantity, and abnormal lymphocyte function. Unlike adult type, its abnormal proliferation mainly occurs in granule single system, and in vitro stem cell culture mainly forms CFU-GM. Chromosome examination is mostly normal, and -7, +8 (8 trisomy) or +21 (21 trisomy) can be seen individually.

Peripheral blood leukocytes increased, platelet reduction and moderate anemia, white blood cells moderately increased, mostly below 100 × 109 / L, immature granulocytes and nucleated red blood cells can appear in the surrounding blood, and there are mononuclear cells, leukocytic Sex phosphatase decreased, even normal, serum and urine lysozyme increased, HbF increased, bone marrow: red for 3 ~ 5:1, granulocyte and mononuclear hyperplasia, erythrocytosis abnormalities, granulocytes at 20 Below 9%, megakaryocytes are reduced, and in vitro bone marrow cell culture is dominated by monocytes.

Because JCML often has fever, hepatosplenomegaly, moderate anemia, leukocytosis, need to be differentiated from infection-induced leukemia, and should be differentiated from infectious mononucleosis.

2. Adult chronic myeloid leukemia

The age of onset is more than 5 years old, more common in 10 to 14 years old, rarely seen in children under 3 years old, the difference between men and women is not big, because it is the malignant proliferation of pluripotent hematopoietic stem cells, so the granules, red, giant nucleus, etc. Department involvement, blast crisis can be converted to lymphocytic leukemia, about 85% of children with Ph1 chromosome (ie t (9:22)), for Ph1 chromosome negative, using molecular biology techniques can be divided into bcr recombination (phbcr + CML) and bcr-free (PH-bcr-cml) two subtypes, the former clinical symptoms are similar to PH1 chromosome positive, the latter clinical symptoms are not typical.

The onset is slow, the symptoms are mild at the beginning, manifested as fatigue, weight loss, bone and joint pain, signs of spleen, liver enlargement, mild lymph nodes, optic nerve head edema, etc., rarely bleeding symptoms.

The peripheral blood picture is mainly leukocytosis, 80% is above 100×109/L, hemoglobin is about 80g/L, and platelets are increased. The classification shows that the granules increase, including acidophilus, basophils, and granulocyte increase is not obvious. In the middle, late and mature granulocytes, white blood cell alkaline phosphatase decreased, HbF did not increase, serum immunoglobulin did not increase, bone marrow hyperplasia was active, mainly granulocyte proliferation, granulocyte <10%, mostly In the middle and late myelocytes and rod-shaped nucleated cells, the granule: red is 10 to 50:1. In some patients, bone marrow fibrosis can be seen, bone marrow megakaryocytes are significantly increased, mature megakaryocytes are dominant, serum and urinary lysozyme are not increased. However, the carrier protein of VitB12 and VitB12 increased, and the colonies and colonies of bone marrow culture increased.

Examination of chronic myeloid leukemia

1. Blood picture: The white blood cell count is higher than 100×109/L. Most of the blood samples are neutral rod-shaped nucleus and late-myelocytes, and the rest are lobular nucleus, medium and young granules, early granules and a few primordial granulocytes. Eosinophils and basophils also increased, early hemoglobin and red blood cells were slightly reduced, platelets were normal or increased, and late red blood cells and thrombocytopenia were identified in the blood picture.

2. Bone marrow: The bone marrow is hyperplasia to hyperactivity. The cell classification is similar to that of the surrounding blood. In the bone marrow slices, granulocytes can be seen in various stages, among which medium and late granules are dominant, and the granulocytes and early granules are more normal than normal. , but generally not more than 5% to 10%, eosinophilic and/or basophilic granulocytes, red blood cell line relatively reduced, grain: red about 10 to 50:1, young red blood cells and megakaryocytes often increase early, late reduction 90% of patients with mature neutrophil alkaline phosphatase activity was significantly reduced.

3. Chromosome examination: Ph' chromosome is found in more than 90% of patients with chronic granules. Ph' chromosome is considered to be a tumor marker of slow pluripotent stem cells. A few chronic granule patients have negative Ph' chromosome, according to the presence or absence of Ph' chromosome. The slow granules are Ph' positive and Ph' negative, and the former has a better prognosis than the latter.

4, blood biochemistry: serum vitamin B12 concentration and vitamin B12 binding capacity is significantly increased as one of the characteristics of this disease, the increase is proportional to the degree of leukocytosis, the increase is due to a large number of normal and leukemia granulocytes produced excessive transport The transcobalt protein I of vitamin B12, serum uric acid concentration can be increased, especially during chemotherapy.

Diagnosis and diagnosis of chronic myeloid leukemia

diagnosis

Diagnosis can be based on medical history, clinical symptoms, and laboratory tests.

Differential diagnosis

1, other causes of splenomegaly: schistosomiasis, chronic malaria, kala-azar, cirrhosis, hypersplenism, etc. have splenomegaly, but each disease has their own clinical features of the primary disease, and blood and bone marrow without CML Change, Ph chromosome is negative.

2, leukemia-like reaction: often secondary to serious infections, malignant tumors and other diseases, and the corresponding clinical manifestations of the primary disease, white blood cell count up to 50 × l09 / L, granulocyte cytoplasm often have poisonous particles and vacuoles, Eosinophils and basophils did not increase, NAP response was strongly positive, Ph chromosome was negative, platelets and hemoglobin were mostly normal, and leukemia-like reactions disappeared after primary disease control.

3, myelofibrosis: primary myelofibrosis splenomegaly, leukocytosis in the blood, and the appearance of granulocytes, easily confused with CML, but the number of peripheral blood leukocytes in primary myelofibrosis is generally better than CML Less, more than 30 × l09 / L, and the fluctuation is not large, NAP positive, in addition, young red blood cells continue to appear in the peripheral blood, abnormal red blood cells, especially teardrop-shaped red blood cells are easy to see, Ph chromosome negative, multiple sites Bone marrow puncture dry pumping, bone marrow biopsy reticular fiber staining positive.

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