In recent years, many studies have shown that the HOX gene family involved in the proliferation, differentiation and maturation of hematopoietic progenitor cells. There is a close relationship between the expression of HOX gene family and acute myeloid leukemia (AML). Most of the HOX genes can promote the proliferation and inhibit the differentiation of the hematopoietic progenitor cells, but the mechanism leading to acute myeloid leukemia remains unknown. This review focuses on the relationship between HOX gene and acute myeloid leukemia and the possible mechanisms leading to acute myeloid leukemia.
Animals ; Gene Expression Regulation, Leukemic ; Genes, Homeobox ; Humans ; Leukemia, Myeloid, Acute ; genetics

Epigenetics indicates the heritable changes in gene expression without nucleotide sequence variation. Leukemogenesis is closely related to abnormal epigenetic regulation. MicroRNA is a non-coding microRNA which regulates the expression of target mRNAs at both transcriptional and translational levels. MicroRNA plays a key role in leukemogenesis when being expressed abnormally in blood cells. MicroRNA in the field of epigenetics became a new hot topic of research on abnormal epigenetic regulation in leukemia genesis. In this article, the abnormal epigenetic regulation and leukemogenesis, the role of miRNA abnormal expression in leukemogenesis, the useful perspective of miRNA in diagnosis, classification, therapy and assessment of leukemias are reviewed.
Epigenesis, Genetic ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia ; genetics ; MicroRNAs ; genetics

A number of studies have demonstrated that the methylation of Dickkopf-1 (DKK1) gene promoter is related with the occurrence and development of many neoplastic diseases. By means of binding with corresponding receptors, DKK1 blocks the transduction pathway of Wnt/β-catenin/TCF and inhibits the proliferation and invasion of tumor cells, inducing apoptosis. Leukemia is a hyperplastic disease of hematopoietic stem cell malignant clone. Its pathogenesis has been confirmed to be closely related with the aberrant activation of Wnt signaling pathway. This pathway is associated with the self-renewal and proliferation of the hematopoietic stem cells, which can regulate growth, differentiation, migration of the cells, angiogenesis and embryonic development. Its expression is regulated by some suppressor genes like Dickkopf 1 (DKK1). Leukemia often accompanied by methylation modification of the DKK1 gene, so as to leads to silencing itself and activation of the Wnt signaling pathway, which cause the occurrence of leukemia. Some therapeutic methods on leukemia aiming at DKK1 gene have been reported, among which DKK1 gene was demethylated. The intensive study on the expression and function of DKK1 should be important for the early diagnosis, treatment and prognosis. This article reviews the current progress in this field.
Apoptosis ; Cell Differentiation ; Gene Expression Regulation, Leukemic ; Humans ; Intercellular Signaling Peptides and Proteins ; Leukemia ; Wnt Proteins ; Wnt Signaling Pathway ; beta Catenin

The aim of the research was to find the up-regulated microRNA (miRNA) in K562 cells treated by 5-aza, to detect the miRNA expression in healthy people, CML patients and leukemia cell lines and to investigate the influence of miRNA on K562 cell proliferation. Up-regulated miRNA in K562 cells after 5-aza treatment was screened by microarray. The up-regulated miR-638, miR-663 and miR-92b with CpG islands in upstream region were screened by microarray in combination with bioinformatics. The miRNA mentioned above was further ascertained by SYBR-green real-time PCR. Up-regulated miR-663 was confirmed by real-time PCR. Expression level of miR-663 was detected in K562, U937 and Kasumi cell lines, and white blood cells from bone marrow of normal donor and from peripheral blood of newly diagnosed CML patient. Methylation-specific PCR (MSP) was applied to analyze the methylated status of miR-663 CpG island in K562 cells. Proliferation of K562 cells was observed after miR-663 was over expressed by transient transfection. The results showed that the expression level of miR-663 in K562 cells was up-regulated after 5-aza treatment, and the expressions of miR-663 were lower in K562, U937, Kasumi cell lines and newly diagnosed patients, compared with healthy people. The CpG island of miR-663 was methylated in K562 cell line according to detection result of MSP. The proliferation of K562 cell could be suppressed by over-expression of miR-663 in vitro. It is concluded that miR-663 CpG island is methylated in K562 cell line. The miR-663 is down-regulated in K562, U937, Kasumi cell lines and CML patients, compared with healthy people. miRNA-663 in K562 cells is up-regulated after 5-aza treatment. Over-expression of miR-663 can suppress the proliferation of K562 cells, which suggests that miR-663 may possesses suppressive effect for leukaemia.
Cell Proliferation ; CpG Islands ; DNA Methylation ; Gene Expression Regulation, Leukemic ; Humans ; K562 Cells ; Leukemia ; metabolism ; pathology ; MicroRNAs ; genetics ; U937 Cells

To explore the expression spectra of apoptosis-related gene pnas-2 in normal tissues and acute leukemia (AL) patient tissues, the expressions of pnas-2 gene in tissues including heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, lymph node, thymus, leukocyte, bone marrow and fetal liver were detected by Northern blot. The expressions of pnas-2 in samples including 44 de novo, 9 non-CR, 27 CR and 12 relapsed AL patients were measured by real-time RT-PCR and Northern blot, and the expression levels of pnas-2 in normal and tumor tissues from 31 patients with malignancies were also detected. The results showed that pnas-2 was not expressed in the most tissues except in placenta. The results of real-time PCR indicated that pnas-2 expressions in samples of de novo, non-CR and relapsed patients ware significantly higher than that in CR, tumor tissues and normal tissues. In serial monitoring of 7 AL patients, the expression level of pnas-2 was high at first visit examination, but remarkably decreased after remission, and the pnas-2 expression level increased again when relapsed. It is concluded that the pnas-2 is specifically up-regulated in acute leukemia patients, which might be an oncogene and participate in leukemogenesis.
Acute Disease ; Apoptosis ; genetics ; Apoptosis Regulatory Proteins ; genetics ; metabolism ; Biomarkers, Tumor ; genetics ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia ; pathology

Lymphoid enhancer factor 1 (LEF1) is a key transcription factor in Wingless-type (Wnt) pathway. The present study was aimed to explore the genetic mutation and expression of LEF1, and their clinical significance in adult patients with acute lymphocytic leukemia (ALL). Genomic DNA was amplified and sequenced to detect the mutation of LEF1 in 131 newly diagnosed adult patients with ALL. Quantitative PCR (qPCR) was performed to detect the expression of LEF1. Moreover, the correlations between mutations and expression of LEF1 with clinical characteristics were analyzed. The results showed that the frequency of LEF1 mutation in adult ALL was 3.1% (4/131) and all of them were point mutations located in exon 2 and 3; the median white blood cell count and median percentage of blasts at diagnosis were significantly higher in LEF1 high expression group than in low expression group (70.6 × 10⁹/L vs 26.2 × 10⁹/L)(P = 0.010); (81.0% vs 57.0%) (P = 0.014); in addition, the percentage of patients with Philadelphia chromosome positive and patients in high-risk group significantly increased in LEF1 high expression group compared with that in low expression group (66.7% vs 36.5%) (P = 0.038); (79.2% vs 56.2%) (P = 0.044). It is concluded that high expression of LEF1 may play an important role on development of adult ALL.
Adult ; Exons ; Gene Expression Regulation, Leukemic ; Humans ; Lymphoid Enhancer-Binding Factor 1 ; genetics ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics

OBJECTIVETo investigate the mechanism of refractoriness of acute myeloid leukemia (AML) by studying the changes of gene mRNA expression from primary diagnosis to relapsed disease in AML.

METHODSDifferences in gene expression profile of bone marrow mononuclear cells were compared between primary diagnosis and relapsed/refractory disease in 3 patients with M(2a) subtype of AML using Agilent human 1B 60mer oligonucleotide microarray.

RESULTSCommon alterations were found in 10 genes among the 20173 genes tested at relapsed/refractory disease as compared with that at primary diagnosis in 3 patients. Of these 10 genes, 7 were up-regulated while 3 down-regulated at relapse in all the 3 patients.

CONCLUSIONDevelopment of relapsed/refractory disease in AML-M(2a) might be associated with the mRNA expression changes in the 10 genes tested including DAPK1. The alteration of these genes may be indications for the early diagnosis of refractoriness of AML, and these genes might provide new therapeutic targets for the treatment of refractory AML.

Adult ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia, Myeloid, Acute ; genetics ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis

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 explore the effect of combined application of psoralen (PSO, an extract from psoralea) and ultraviolet A (UVA) for inducing the apoptosis of human leukemic cell line NB4 and its impact on the Fas/FasL gene expressions.

METHODSAccording to factorial design, changes of apoptosis rate and ultrastructure of NB4 cells, as well as the gene and protein expressions of Fas/FasL were observed after cells were treated with PSO in different concentrations and irradiated by UVA of 360 nm wavelength for different times, using flow cytometry, transmission electron microscopy and quantitative polymerase chain reaction (PCR), and the outcomes were treated with variable analysis.

RESULTS(1) After treatment of PSO in concentration of 10, 20, 40, 80 microg/mL combined with a 5-min exposure of UVA, the NB4 cells apoptosis rate induced were 26.57% +/- 0.42%, 30.67% +/- 0.11%, 34.90% +/- 0.30% and 24.63% +/- 0.38% respectively. The effects were dose- and time-dependent, and an interaction was shown between the two actors. (2) After being treated by PSO plus UVA, obvious ultrastructure changes with apoptosis characteristics were shown in NB4 cell under electron microscope. (3) PSO plus UVA showed up-regulatory effect on gene and protein expressions of Fas, and down-regulatory effect on gene and protein expressions of FasL in a dose- and time-dependent manner, with the interaction between the two actors in altering Fas gene expression, also in altering FasL gene and protein expressions.

CONCLUSIONCombined application of PSO and UVA can induce the apoptosis of NB4 cells, and the Fas/FasL system is one of the pathways for apoptosis inducing.

Apoptosis ; drug effects ; radiation effects ; Cell Line, Tumor ; Fas Ligand Protein ; metabolism ; Ficusin ; pharmacology ; Gene Expression ; Gene Expression Regulation, Leukemic ; Humans ; Ultraviolet Rays ; fas Receptor ; metabolism

OBJECTIVETo investigate the effect of up-regulated expression of tumor suppressor gene p14(ARF) on apoptosis of chronic myeloid leukemia (CML) cells and its interaction with imatinib.

METHODSTumor suppressor gene p14(ARF) was transduced into K562 (K562-p14(ARF)) and 4 blast crisis primary CML cells (CML-BC 1-4) using vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentiviral vector with cells transduced by empty vector as control. Fluorescence microscopy and flow cytometry were applied to measure transduction efficiency, and Western blotting assay was used to detect p14(ARF) protein of K562 cells. WST-8 method was used to determine cell growth inhibition rate of K562 cells transduced by the target gene under different concentrations of imatinib (0, 0.015, 0.062, 0.125, 0.25, 0.5, 1.0, 2.0 μmol/L). Cell apoptosis and leukemic cellular colony-forming ability were detected by Annexin V-FITC/PI dyeing using flow cytometry (FCM) and semi-solid culture method respectively.

RESULTSFluorescence microscopy and FCM showed that transduction efficiency (GFP positive cells) of K562-p14(ARF), K562-VSV and CML-BC1 cells were close to 100%, and CML-BC 2-4 cells were 80% to 90% on average. Results of Western blotting showed that the levels of ARF protein expression of K562 cells transduced by p14(ARF) were significantly higher than of untransduced cells; the apoptosis rate of K562-p14(ARF) was 20%; the mean apoptosis rate of 4 primary leukemic cells transduced by the p14(ARF) [(71.1±22.4)%] was significantly higher than of control group [(12.4±6.2)%] (P<0.05). Imatinib significantly inhibited the proliferation of K562-p14(ARF) cells in a dose-dependent manner. The mean leukemic cellular colony-forming unit of 4 primary leukemic cells transduced by the p14(ARF) (41.5±13.2) was significantly lower than of the control group (88.5±7.9) (P<0.05).

CONCLUSIONIncreased p14(ARF) gene expression could induce apoptosis of CML cells; Moreover, it could enhance inhibitory effect on cell proliferation when combined with imatinib.

Apoptosis ; Gene Expression Regulation, Leukemic ; Genetic Vectors ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; metabolism ; pathology ; Tumor Suppressor Protein p14ARF ; metabolism ; Up-Regulation