Humans ; Blast Crisis/genetics* ; Leukemia, Promyelocytic, Acute/genetics* ; Oncogene Proteins, Fusion/genetics* ; Tretinoin

Chronic myeloid leukemia is a myeloproliferative disorder characterized by excessive cloning of bone marrow multipotent stem cells. According to the disease course, the CML may be divided into chronic phase (CP), accelerated phase (AP) and blastic phase (BP). At present, the molecular mechanisms of acute transformation of CML has not been fully understood. The recent studies have shown that the epigenetics is one of mechanisms in blastic transformation of CML, including three molecular mechanisms such as DNA modification, histone modifications and RNA-related dysregulation. The molecular mechanisms for epigenetics leading to the transformation of CML are discussed in this review.
Blast Crisis ; genetics ; Disease Progression ; Epigenesis, Genetic ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics

OBJECTIVETo study the gene expression profile of chronic myeloid leukemia (CML) in chronic and blast phases for providing information about the potential mechanisms of blastic crisis.

METHODSThe gene expression difference of bone marrow mononuclear cells between CML in chronic and in blastic phases was examined with DNA array.

RESULTSIn the blastic phase, 68 genes were obviously up-regulated in the 1176 tested genes. Among the 68 genes, the transcription factors accounted for 23.5%, cell surface antigens 22.1%, regulation proteins 19.1% and others 35.3%. There were 17 genes expressed only in the blastic phase and 11 (16.2%) genes related to G protein.

CONCLUSIONSObvious difference of gene expression profile existed between chronic and blastic phases of CML. Up-regulation of gene expression is one of the characteristics of CML in blastic phase. The genes related to G protein may play an important role in the blastic transformation of CML.

Blast Crisis ; genetics ; metabolism ; Bone Marrow Cells ; metabolism ; Cells, Cultured ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Male

To investigate the karyotype of chronic myeloid leukemia in blast crisis (CML-BC), karyotype analysis was performed with R-banding technique in 119 patients with CML-BC. Dual fusion fluorescence in situ hybridization (FISH) was used to detect derivative chromosome 9 deletions in randomly selected 28 cases of them. The results showed that 11 cases (8.9%) were Ph negative; 113 cases (91.1%) were Ph positive; 104 cases (83.9%) had standard Ph translocation; 9 cases (7.2%) showed variant translocation, including 4 cases (3.2%) with simple variant translocation and 5 cases (4.0%) with complex variant translocation. 72.6% of Ph negative CML-BC had extra chromosomal abnormalities, with the most common ones being i (17q) and +14. 72.3% of Ph positive CML-BC had extra cytogenetic changes and +Ph, +8, i (17q) were the most frequent. The average time between diagnosis and blast crisis was 29.0 months (range 2 to 66 months) for Ph negative cases and 34.2 months (range 1 to 127 months) for Ph positive cases. 5 cases (5/28, 17.9%) with der (9) deletions were detected by FISH technique. It is concluded that extra chromosomal abnormalities are common in CML-BC patients and FISH can effectively detect the der (9) deletions.
Adult ; Blast Crisis ; genetics ; Chromosome Deletion ; Chromosomes, Human, Pair 9 ; genetics ; Female ; Humans ; Karyotyping ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Male

OBJECTIVETo identify differentially expressed genes between chronic phase and blast crisis in chronic myeloid leukemia, explore the mechanism and screen potential biomarkers of disease progression.

METHODSThe differences in the gene expression profiles of bone marrow mononuclear cells between chronic phase and blastic crisis were examined using DNA microarray. PANTHER database, Genomatix database and Bibliosphere software were used to analyze and predict the critical genes or transcription factors during disease progression. Some of the genes or transcription factors were selected for verification by semi-quantitative RT-PCR.

RESULTSIn blastic crisis, 68 of the 1176 tested genes were obviously up-regulated. Sixteen of these differential genes were selectively expressed in leukocyte membranes. CD40, CCR3, LGALS3, RGS3, CEACAM3 and the related transcription factors RAC1, CTNNB1, TP53, and NF-κB, all as the nodes of the entire regulatory network, were presumed to play key roles in disease progression. The results of RT-PCR were consistent with the microarray data and showed high expression of CEACAM3, RGS3, CTNNB1 and RAC1 in blastic crisis.

CONCLUSIONA group of genes have been identified to very likely play key roles or serve as biomarkers in the transition from the chronic phase to blastic crisis in chronic myeloid leukemia.

Blast Crisis ; genetics ; Computational Biology ; Gene Expression Profiling ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Oligonucleotide Array Sequence Analysis ; Transcriptome

OBJECTIVETo investigate the value of multiplex fluorescence in situ hybridization (M-FISH) for the detection of complex chromosomal abnormalities (CCA) of chronic myeloid leukemia in blast crisis (CML-BC).

METHODSM-FISH was used to study 26 cases of CML-BC with CCA assayed by conventional cytogenetics (CC).

RESULTSSixty-nine kinds of structural rearrangements were detected by M-FISH besides typical t (9;22) translocation, among them only 10 were balanced ones and 59 unbalanced ones including 1 insertion, 6 deletions, 52 translocations and derivative chromosomes. In addition, 23 numerical abnormalities were detected. All chromosomes were involved in CML-BC, and chromosomes 17, 2, 8, 16 involvements were the most frequent. M-FISH failed to find out the abnormal clone in 1 case, discovered CCA clones that were missed CC in 6 cases. Clarified 16 kinds of aberrations which could not be identified CC and corrected 5 aberrations made wrong description by CC. Thirty-five kinds of translocations were found by M-FISH which were missed by CC. The aberrations of der (9) t (16; 6; 9; 22) and der (18) t (16; 18; 19) we found were reported in the literature for the first time.

CONCLUSIONSM-FISH can refine CCA in CML-BC, find out or correct the missed or misidentified abnormalities by CC. The frequent secondary chromosomal abnormalities in CML-BC with CCA are different from that in CML.

Adult ; Blast Crisis ; genetics ; Chromosome Aberrations ; Female ; Humans ; In Situ Hybridization, Fluorescence ; methods ; Karyotyping ; Leukemia, Myeloid, Accelerated Phase ; genetics ; Male ; Middle Aged

Acute Disease ; Blast Crisis ; genetics ; Genes, Retinoblastoma ; Genes, Wilms Tumor ; Humans ; Leukemia ; genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; pathology ; Polymerase Chain Reaction ; U937 Cells

OBJECTIVE: To investigate the clinical significance of SCIN gene expression and promoter methylation in patients with chronic myeloid leukemia (CML). METHODS: Real-time quantitative PCR was used to detect the expression level of SCIN in mononucleatr cells of bone marrow samples from 64 CML patients and 37 controls. The methylation levels of SCIN promoter in 65 patients with CML and 29 controls were detected by real-time quantitative methylation-specific PCR and bisulfite sequencing PCR. RESULTS: The expression level of SCIN in CML patients was significantly down-regulated (P＜0.05), compared with the control group. The down-regulation rate of SCIN expression in CML patients at chronic phase, accelerated phase and blast crisis was 61%, 67% and 75%, respectively. Spearman correlation analysis showed that the expression level of SCIN negatively correlated with the transcript level of BCR-ABL1 (R=-0.315, P＜0.05). However, there was no significant difference in clinical parameters such as sex, age, white blood cell count, hemoglobin level, platelet count, chromosome, CML staging and BCL-ABL1 transcript level between low and high SCIN expression groups of CML patients (P＞0.05). No significant difference in methylation of SCIN promoter between CML patients and controls, and no correlation between SCIN expression and promoter methylation were observed (P＞0.05). CONCLUSION The SCIN expression is down-regulated in CML patients, which may relate with the pathogenesis that is, BCR-ABL1 fusion gene induces CML tumorigenesis. The down-regulation of SCIN expression may relate with the progression of CML.
Blast Crisis ; DNA Methylation ; Down-Regulation ; Fusion Proteins, bcr-abl ; Gelsolin ; genetics ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; Promoter Regions, Genetic

OBJECTIVE: To investigate the expression and significance of regulatory T cells (Tregs), FoxP3 and transforming growth factor-β (TGF-β) in different phase of chronic myeloid leukemia (CML). METHODS: Peripheral blood of 73 CML patients in Department of Hematology, Heze Municipal Hospital from March 2018 to March 2021 were collected. According to patient's period in CML, they were divided into ND CML group (newly diagnosed), CP CML group (chronic period), and BP CML group (blast phase). The percentage of Tregs, expression level of FoxP3 mRNA and TGF-β were detected by flow cytometry, RT-qPCR, and ELISA, respecitively. The roles of above indices in clinical pathogenesis of patients with CML were analyzed. RESULTS: The proportion of Treg in the ND CML group was slightly higher than the CP CML group, but the difference was not statistically significant (P =0.695), while the BP CML group was significantly higher than the other two groups (P =0.008, P <0.001). The expression levels of FoxP3 mRNA in ND CML group, CP CML group and BP CML group were 11.61±2.21, 6.46±1.35 and 8.54±2.13, respectively. Significant difference in FoxP3 mRNA levels was observed among patients in different phases of CML (F =55.199, P <0.001). The expression levels of FoxP3 mRNA both in ND CML group and BP CML group were significantly higher than that in CP CML group (P <0.001), and the ND CML group was the highest (P <0.001). However, the expression levels of TGF-β in different phases of CML showed no statistical differences (H =0.634, P =0.728). CONCLUSION The abnormal distribution of Treg subset in different phases of CML and the significant increase of the expression level of FoxP3 mRNA in the new onset and blast phase of CML suggest that Tregs may promote the occurrence and progression of CML through immune regulation.
Humans ; Blast Crisis/metabolism* ; Forkhead Transcription Factors/metabolism* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; RNA, Messenger/metabolism* ; T-Lymphocytes, Regulatory/metabolism* ; Transforming Growth Factor beta/metabolism*

The aim of this study was to investigate the expression status of the helicase antigen (HAGE) transcript and its clinical significance in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). The expression of HAGE cDNA in bone marrow mononuclear cells from AML and CML patients was detected by using real-time quantitative PCR. The results indicated that overexpression of HAGE transcript (117.12% - 9842.70%, median 434.96%) was detected in 14.8% (11/74) AML patients. AML patients with HAGE cDNA expression were significantly older than those HAGE-negative patients (median 67 and 45 years, respectively, p = 0.001). HAGE cDNA expression was more frequently present among the patients with acute monoblastic leukemia (M(4) and M(5), 7 of 20, 35.0%), compared to the patients with acute non-monoblastic leukemia (M(1), M(2), M(3) and M(6), 4 of 54, 7.4%) (p = 0.007). 28.6% (8/28) cases with normal karyotypes showed HAGE cDNA overexpression, significantly higher than 7.5% (3 of 40) in those with chromosomal abnormalities (p = 0.041). Overexpression of HAGE transcript was found in 9 (34.6%) CML cases and more frequently observed at accelerated phase and blast crisis (4/4, 100%) than that at chronic phase (5/22, 22.7%) (p = 0.008). It is concluded that HAGE cDNA expression is relevant to specific subtypes of AML and to the progression of CML.
Blast Crisis ; Bone Marrow Cells ; metabolism ; DEAD-box RNA Helicases ; genetics ; metabolism ; DNA, Complementary ; Gene Expression ; Humans ; Karyotype ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; genetics ; metabolism ; Leukemia, Myeloid, Acute ; genetics ; metabolism ; Neoplasm Proteins ; genetics ; metabolism ; RNA, Messenger ; genetics