ABSTRACT
Histone modification is an important mechanism in oncogenesis and development of hematologic malignancies. Acetylation of lysine residues on histones and opening chromatin are correlated with activation of genes, whereas lysine residues methylation can result in either activation or repression on expressions of chromatin. The main point of all is deacetylation of histone mediated by histone deacetylases (HDACs). HDAC inhibitors are divided into 4 categories: short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides and benzamides, owning different mechanisms in HDAC inhibition. Many kinds of I/II phase clinical tests showed that all these HDAC inhibitors have obviously therapeutic efficacies in treatment of hematologic malignancies with low poisons. Combination of HDAC inhibitors with DNA demethylation drugs can decrease DNA methylation, increase histone acetylation and recover antioncogene expression. As important parts of epigenetics, histone acetylation and HDAC inhibitors possess positive prospects in treatment of hematologic malignancies. In this review the advances of study on mechanisms of histone modification, HDAC inhibitors and their use in treatment of hematologic malignancies are summarized.
Subject(s)
Acetylation , Hematologic Neoplasms , Drug Therapy , Histone Deacetylase Inhibitors , Therapeutic Uses , Histone Deacetylases , Genetics , Histones , Chemistry , Genetics , MetabolismABSTRACT
<p><b>OBJECTIVE</b>To explore the characteristics of CpG islands methylation at promoter region of HOX A gene cluster in leukemia cells before and after all-trans retinoic acid (ATRA) treatment.</p><p><b>METHODS</b>Eleven human leukemia cell lines, bone marrow cells from leukemia patients before and after therapy and white blood cells from normal subjects were collected. HL-60 and K562 cells were treated by 2-deoxy-5-azacytidine (DAC) or ATRA respectively. Bisulfite modified DNA of these cells were amplified with PCR and quantitatively analyzed by pyrosequencing for methylation of CpG islands.</p><p><b>RESULTS</b>In normal cells, CpGs at all loci of HOX A cluster were unmethylated. In HOX A4, A6, A7, A9, A10 and A11, many CpG sites were methylated (>20%) or hypermethylated (>50%) in leukemia cell lines. Percentages of methylated CpGs were higher in T-cell leukemia (71.4%) and B-cell leukemia (85.7%) than in others. For individual CpGs methylations there were HOX A4 in all leukemia cells, HOX A6 and HOX A7 in most of the leukemia samples and HOX A10 and HOX A11 in K562 and HL-60 cells (38%-86%). HOX A9 CpGs showed hypomethylation in most of myeloid leukemia cells, whereas HOX A11 CpGs were hypermethylated in B-cell leukemia (>50%). Methylation levels of HOX A4 and A6 in AML and ALL patients after complete remission were decreased obviously, and so did HOX A6 and A9 in CML patients. Methylation levels of HOX A4, A6 and A10 in HL-60 cells and of HOX A6 in K562 cells were reduced by ATRA treatment.</p><p><b>CONCLUSIONS</b>In all leukemia cell lines, aberrant methylation of CpGs was observed at promoter regions of 6 HOX A cluster genes, and some of these genes showed leukemia-type-specific hypermethylation. CpGs methylation of some HOX A genes in leukemia cell lines, especially in HL-60 cells, were down-regulated by ATRA.</p>
Subject(s)
Humans , Cell Line, Tumor , CpG Islands , Genetics , DNA Methylation , Homeodomain Proteins , Genetics , Leukemia , Genetics , Multigene Family , Promoter Regions, Genetic , GeneticsABSTRACT
<p><b>OBJECTIVE</b>To investigate the effect of ligustrazine (LT) on hematopoiesis in mice after bone marrow isotransplantation (iso-BMT).</p><p><b>METHODS</b>The typical model of iso-BMT was established and the model mice were randomly divided into two groups, the LT group treated with LT injection 0.2 ml and the control group treated with normal saline 0.2 ml, twice a day by gastrogavage. The following parameters were observed in the day 1, 7 and 14: peripheral blood cells, bone marrow mono-nuclear cells (BMMNC), heparin sulfate (HS) expression in bone marrow section by immunohistochemical SABC-AP method, stromal cell derived factor-1 (SDF-1) expression and CXC chemotaxis factor receptor 4 (CXCR4) expression.</p><p><b>RESULTS</b>The levels of peripheral WBC, platelet, BMMNC, CXCR4, HS, SDF-1 at the day 7 and 14 in the LT group were all higher significantly than those in the control group (P < 0.05 or P < 0.01).</p><p><b>CONCLUSION</b>LT could improve the bone marrow hematopoiesis in the early hematopoietic re-establishing stage after BMT.</p>