juvenile chronic myeloid leukemia
Introduction
Introduction to juvenile chronic myeloid leukemia Juvenile chronic leukemia is rare in children, the majority of which are chronic myeloid leukemia (slow granule, CML). The clinical and biological characteristics of CML in infants are significantly different from those of adult CML. The disease is characterized by elevated white blood cells and splenomegaly. basic knowledge The proportion of illness: 0.002% Susceptible people: children Mode of infection: non-infectious Complications: anemia
Cause
The cause of juvenile chronic myeloid leukemia
(1) Causes of the disease
Ph1 is a signature chromosomal change in CML. It is formed by non-random t(9;22)(q34;q11). There is a c-abl gene at the breakpoint of chromosome 9, its variability can be greater than 100kb, and the bcr gene is located at 22 Chromosome, a small 5.8 kb small fragment of variability, forms a bcr/abl fusion gene at the 22q- and 9q junctions after translocation, encoding a specific 210 kb protein (P210), a tyrosine kinase It plays a role in the pathogenesis of tumors, and the Ph1 chromosome has its special condition in children's CML.
1. Ph1 negative CML 5% ~ 10% have typical CML, clinical manifestations of Ph1 negative, may have the following reasons:
(1) Other chromosomal fragments bind to 22q, making 22q- of Ph1 not readily detectable at cytogenetic levels.
(2) Chromosome 9 has a break or gene rearrangement, but 22q11 is not broken, and molecular biology techniques can detect these changes when CML Ph1 is negative.
2. Ph1-positive acute leukemia: Ph1 chromosome is not only present in CML, 3% to 10% of children with acute leukemia have Ph1 chromosome, Ph1-positive acute leukemia can be CML blast, or may be primary acute leukemia, in clinical and It is difficult to distinguish these two conditions in hematological examination, but cytogenetics combined with molecular biology techniques can be found that Ph1-positive acute leukemia is often a non-CML-specific non-random chromosomal abnormality t(9;22)(q34;q11) There is a gene rearrangement other than the bcr gene, and a 190 kb protein (P190) is produced. The Ph1 chromosome and P190 in the bone marrow cells disappear after treatment remission, while the CML is reversed, and there is a CML-specific non-random chromosomal abnormality t (9). ;22) (q34; q11), the 210 kb protein (P210) produced by the Ph1 chromosome and bcr gene rearrangement is always present at any stage of the disease.
(two) pathogenesis
The pathogenesis of CML is still unknown. It is generally considered to be a pluripotent hematopoietic stem cell disease. Its occurrence has certain relationship with certain chemical substances and genetic factors. In 1960, Nowell and Hungerford discovered the Ph chromosome in CML patients in Philadelphia for the first time. Most scholars currently It is believed that the Ph chromosome has special significance for the diagnosis of CML, and the positive rate is 70%-90%. In 1973, Rowley determined that the Ph chromosome is formed by the translocation of chromosomes 9 and 22, ie t(9:22) ( Q34:q11), this chromosomal translocation is known to fuse the proto-oncogene C-ab1 normally located on 9q34 with the bcr oncogene on 22q11 to express BCR- with high tyrosine protein kinase (PTK) activity. ABL fusion protein, which is considered to be the molecular basis of the pathogenesis of CML. In the past two years, the pathogenesis of CML, the diversity of BCR-ABL fusion protein and its relationship with leukemia phenotype have been deepened at the molecular level abroad. In the study, three BCR-ABL fusion gene rearrangements have been discovered, because the precise location of the ABL gene breakpoint is variable, and can occur in any segment of the gene 5' end > 300 kb, and the BCR gene breaks. Point cluster There are mainly three, so the BCR-ABL fusion gene is divided into three main types according to the position of the BCR gene breakpoint: M-bcr, m-bcr, -bcr and 6 BCR-ABL, and the fusion transcription mode: b2a2, b3a2, B3a3, b2a3, e1a2, e19a2.
1. M-bcr: BCR gene breakpoint is in the 5.8 kb major breakpoint cluster, ie, the 12-165 exon region of this gene, and the fusion transcription pattern with ABL gene is b2a2, b3a2, b3a3, b2a3, coding The protein is P210. This type is found in most CML and some acute lymphoblastic leukemia (ALL). P210 CML mainly involves granules. Most of the cell maturation is blocked in the middle and late granule stages, while in the erythroid, mononuclear and lymphoid tissues. The impact is small.
2.m-bcr: The BCR breakpoint is located in the farther upstream region, in the 54.4 kb intron between exons e1 and e2, called the secondary bcr, and the ABL fusion transcription mode is ela2, encoding the fusion protein. P190, this type is found in very few CML and most ALL. P190 can affect both granules and single cell lines. It shows absolute and relative mononuclear cells, mature neutrophils, low single cell ratio, and varying degrees of basophilicity. With neutrophils, the proportion of immature granulocytes in peripheral blood is relatively high, and the neutrophil alkaline phosphatase score is low.
3.-bcr: The BCR breakpoint is located between the exons e19 and e20, which is called the 3'-end BCR breakpoint. The fusion with ABL is e19a2, which encodes the fusion protein P230, which is found in very few slow-granular and chronic neutrals. Granulocyte leukemia (CNL), the main feature of this type is mature neutrophil hyperplasia, which is characterized by "hidden or benign" clinical process, and has a long survival period. Ph cells may adhere to abnormal changes of BCR-ABL fusion protein. The ability of bone marrow stromal cells and other extracellular matrix components to decrease, allows immature cells to be released from the bone marrow into the blood, thereby allowing immature cells to escape the normal regulation of proliferation and differentiation of the bone marrow matrix microenvironment.
The study also found that 5% to 10% of Ph chromosomes were negative in patients with CML. Ph chromosome negative patients did not find t(9;22) in cytogenetics, but Ph chromosome negative (Ph-CML) was separable at the molecular level. For the two subtypes of bcr recombination (Ph-bcr CML) and no bcr recombination (Ph-bcr-CML), most Ph-CML patients are Ph-bcr CML, and Ph-bcr-CML patients are only a few, some authors It is believed that the latter may be chronic granuloma leukemia (CMML). Molecular biological techniques are of great significance for the classification of Ph-CML, and have certain value for the diagnosis, treatment and estimation of prognosis of patients. Ph-bcr CML and Ph are considered. CML has the same clinical, hematological, and acute changes in the same way, the treatment of -interferon (IFN-a) is better; while the clinical and hematological performance of Ph-bcr-CML patients are not Typically, the efficacy of IFN-a is also poor. CML is usually divided into three phases, namely chronic phase, accelerated phase and malignant phase. The latter is the main cause of death. The only effective treatment is bone marrow transplantation (BMT), especially chronic. The efficacy of the period is significantly better than the advanced stage, therefore, choosing the most appropriate BMT time is the key to long-term survival of patients. Yes, there is still no reliable method to predict the time of malignant transformation. In recent years, a new molecular gene marker, the abnormal methylation of the calcitonin (CT) gene of the short arm (11P) of chromosome 11 has been reported in foreign countries. CML deterioration can be monitored, and studies have found that in the chronic phase, most of the normal methylation, but can be converted to hypermethylation during the disease progression, this hypermethylated HpaII fragment (3.1Kb) will prompt CML at an average of 6 Malignant transformation will occur within a month (before clinical manifestations and morphological malignant transformation). Therefore, hypermethylation of CT gene can be used as a molecular marker for clinical monitoring of disease progression. Through continuous analysis of CT gene methylation status, Clinical BMT selects patients and provides time to provide evidence.
Prevention
Juvenile chronic myeloid leukemia prevention
1. Avoid contact with harmful factors: pregnant women and children should avoid exposure to harmful chemicals, ionizing radiation and other factors that cause leukemia. When exposed to poisons or radioactive materials, various protective measures should be strengthened; avoid environmental pollution, especially indoor environmental pollution; Pay attention to the rational use of drugs, use cytotoxic drugs with caution.
2. Vigorously carry out prevention and treatment of various infectious diseases, especially viral infectious diseases, and do a good job of vaccination.
3. Do a good job in eugenics to prevent certain congenital diseases, such as 21-trisomy, Fanconi anemia, etc.
Complication
Juvenile chronic myeloid leukemia complications Complications anemia xanthomas
Often complicated by repeated infections, hemorrhage, severe anemia, hepatosplenomegaly and bone pain, can be complicated by xanthoma and eczema-like dermatitis, but also complicated by multiple milk brown rash (common in neurofibroma) and so on.
Symptom
Symptoms of juvenile chronic myeloid leukemia Common symptoms Lymph node enlargement Abdominal pain, weak bone pain, low heat, weight loss, hemorrhagic tendency, hepatosplenomegaly, repeated infection
The age of onset is <4 years old, mostly 1,2 years old, the onset is acute, the course of disease is short, similar to AL, the initial symptoms are often repeated infection, followed by bleeding, ecchymosis, rash, abdominal pain, bone pain and liver and spleen lymph nodes Moderately enlarged, juvenile chronic myeloid leukemia involves multiple hematopoietic stem cells, and the number of peripheral white blood cells is increased, which is characterized by fever, hepatosplenomegaly, rash, hemorrhage, weight loss, etc., and the number of white blood cells is often (15-85). ×109/L (15,000 ~ 85,000 / mm3); the number of platelets is usually (25 ~ 100) × 109 / L (25,000 ~ 100,000 / mm3); hemoglobin value is usually 80 ~ 100g / L granulocytes in the bone marrow Systemic hyperplasia is extremely active, megakaryocytes are reduced, immature granulocytes, immature monocytes and nucleated red blood cells can be seen in the surrounding blood. There may be xanthoma and eczema-like dermatitis. In addition, multiple milky brown rashes can be seen ( Common in neurofibroma, fetal hemoglobin (HbF) is often elevated, with an average of 38%, and some as high as 70%, but there are also those who do not rise, Ph1 chromosome is negative.
Examine
Examination of juvenile chronic myeloid leukemia
1. Blood test: juvenile chronic myeloid leukemia involves multiple hematopoietic stem cells, and there are severe anemia in peripheral blood. Reticulocytes increase, peripheral white blood cell count increases (15-100)×109/L, white blood cell count white blood cell classification Neutral, young, lobular granulocytes, basophils do not increase, thrombocytopenia, alkaline phosphatase activity is reduced, compared with CML, the following characteristics: peripheral blood mononuclear cell ratio >10% The proportion of naive cells is <5%; Hb-F is elevated; hypergammaglobulinemia, MDS with Chromosome 7 is similar to JCML, but Hb-F is not high.
2. Bone marrow: The immature mononuclear cells of the bone marrow increased, the proportion of immature cells was <30%; there was no special morphological abnormality, and the neutrophilic granulocytes were significantly proliferated, and the erythroid and megakaryocytes were reduced.
3. Others: Ph chromosome negative, fetal hemoglobin increased (40% to 60%, a few <9%), hemoglobin A2 decreased.
Diagnosis
Diagnosis and diagnosis of juvenile chronic myeloid leukemia
diagnosis
There is no uniform diagnostic criteria for pediatric chronic granules. The diagnostic criteria for adult chronic granules were set at the Second National Leukemia Treatment Symposium held in Guiyang in 1989.
Chronic period of CML
(1) Clinical manifestations: asymptomatic or low fever, fatigue, sweating, weight loss and other symptoms.
(2) blood routine: white blood cell count increased, mainly in neutral, young and rod-shaped granulocytes, blast cells (type I type II) 5% to 10%, eosinophils and basophils, There may be a small amount of nucleated red blood cells.
(3) Bone marrow: hyperplasia is extremely active, mainly granulocyte hyperplasia, middle, late granules and rod-shaped granulocytes, primordial cells (type I type II) 10%.
(4) Chromosome: There is a Ph chromosome.
(5) cFu-GM culture: colonies or clusters increased significantly compared with normal.
2. Accelerated period of CML has the following two, can be diagnosed:
(1) Unexplained fever, anemia: increased bleeding, and/or bone pain.
(2) Progressive swelling of the spleen.
(3) It is not due to the progressive reduction or increase of platelets caused by drugs.
(4) The original cells (type I type II) are >10% in the blood and/or bone marrow.
(5) Peripheral blood basophilic cells >20%.
(6) Significant collagen fibrosis in the bone marrow.
(7) Other chromosomal abnormalities other than Ph.
(8) Ineffective for traditional anti-slow granule drugs.
(9) CFU-GM has defects in proliferation and differentiation, clustering increases, and the ratio of clusters and colonies increases.
3. blastic crisis of CML with one of the following can be diagnosed:
(1) The original granulocytes (type I type II) or the original leaching plus young drench, or the original single plus young single in the peripheral blood or bone marrow 20%.
(2) The primary particles plus promyelocytes in the peripheral blood are 20%.
(3) The primary particles in the bone marrow plus promyelocytes are 50%.
(4) Extramedullary primordial cell infiltration.
Differential diagnosis
1. Identification of combined immunodeficiency or congenital virus infection: Younger type chronic particles need to be differentiated from combined immunodeficiency or congenital virus infection, especially persistent EB virus infection, and similar to the clinical manifestations of juvenile slow granules. However, these diseases do not have high fetal hemoglobin levels in young children.
2. Familial chronic granulocytic leukemic syndrome: Smith et al (1974) reported that two pairs of siblings have familial chronic myeloid leukemia syndrome, and their clinical manifestations are similar to those of juvenile chronic granules, but Its survival period is significantly longer than that of young children.
3. Identification of JCML and CML.
