Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HOXA5 is a member of the HOX gene family, which is known to play key roles during embryonic development and in differentiation of adult cells. In addition, HOXA5 has been implicated as a tumour suppressor in breast cancer and shown to transactivate the p53 gene. CpG island methylation is a common mechanism of gene inactivation in tumour cells, but is rarely involved in control of cell-type-specific (CTS) expression in normal cells. However, here we demonstrate that HOXA5 is one of a small number of genes whose CTS expression pattern is controlled by CTS CpG island methylation in normal cells. Furthermore, chromatin immunoprecipitation analysis identified novel patterns of histone modifications associated with DNA methylation of HOXA5. High levels of methylation of histone residues (lysine 9 and 36 of histone H3) previously associated with transcriptional repression were present in the unmethylated, actively transcribing state, and were then reduced following DNA methylation and gene inactivation. Alterations to the normal patterns of HOXA5 gene methylation were also observed in tumour cells. Quantitative analysis of HOXA5 methylation identified the presence of limited methylation in all of the breast, lung and ovarian tumours examined. However, methylation levels in these three tumour types were nearly always low and comparable with that detected in the corresponding normal tissue. In contrast, acute myeloid leukaemia (AML) samples frequently (60% of samples) exhibited very high methylation levels, far greater than that seen in normal haematopoietic cells, suggesting a role for hypermethylation of HOXA5 in the development of AML, consistent with its previously identified role in haematopoietic differentiation.
Carcinogenesis 2007 Feb
PMID:HOXA5 is targeted by cell-type-specific CpG island methylation in normal cells and during the development of acute myeloid leukaemia. 1686 Dec 63

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism and DNA methylation. Studies on MTHFR polymorphism in leukemia have largely focused on the protective role of MTHFR polymorphism in acute lymphoblastic leukemia (ALL). We evaluated the C677T and A1298C polymorphisms using the TaqMan allelic discrimination assay in various malignancies. The study population included 115 subjects with chronic myelogenous leukemia (CML), 200 with acute myelogenous leukemia (AML), 196 with multiple myeloma (MM) and 434 healthy control subjects. The frequency of 1298CC was statistically significantly higher in subjects with CML than that of the controls (OR=5.12, 95% CI: 1.75-14.9, P-value=.003). Of note, the frequencies of 677CC/1298CC genotype were statistically significantly higher in subjects with CML, AML and MM than that of the controls (OR=8.8, 3.5, 3.83, P-value=.002, 0.036, 0.023, respectively). Our results demonstrate that the MTHFR 1298CC homozygote variant is strongly associated with an increased risk of CML, while MTHFR C677T does not significantly affect the risk of CML. Moreover, we demonstrated that MTHFR 677CC and 1298CC genotype might have combined effect on risk of CML, AML and MM and it is inferred that the A1298C may play a different role in carcinogenesis, depending on the types of organs involved, the types of disease entities and the genotype of C677T.
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PMID:MTHFR 677CC/1298CC genotypes are highly associated with chronic myelogenous leukemia: a case-control study in Korea. 1715 40

Ki-ras gene mutations that specifically occur in codons 12, 13 and 61 are involved in the carcinogenesis of acute myeloid leukemia, melanoma and different carcinomas. In order to define potential mutation-specific therapeutic targets, stable transfectants of NIH3T3 cells carrying different Ki-ras4B gene mutations were generated. Wild type Ki-ras transformants, mock transfectants and parental cells served as controls. These in vitro model systems were systematically analyzed for their protein expression pattern using two-dimensional gel electrophoresis followed by mass spectrometry and/or protein sequencing. Using this approach, a number of target molecules that are differentially but coordinately expressed in the ras transfectants were identified next to other proteins that exhibit a distinct regulation pattern in the different cell lines analyzed. The differentially expressed proteins predominantly belong to the families of cytoskeletal proteins, heat shock proteins, annexins, metabolic enzymes and oxidoreductases. Their validation was assessed by real-time quantitative RT-PCR and/or Western blot analysis. Our results suggest that the Ki-ras-transformed cells represent a powerful tool to study Ki-ras gene mutation-driven protein expression profiles. In addition, this approach allows the discovery of ras-associated cellular mechanisms, which might lead to the identification of physiological targets for pharmacological interventions of the treatment of Ki-ras-associated human tumors.
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PMID:Influence of Ki-ras-driven oncogenic transformation on the protein network of murine fibroblasts. 1721 28

Regulation of normal cell growth and turnover is balanced between cell proliferation, cell differentiation and apoptosis.A disruption of this balance is thought to be an important event leading to carcinogenesis .One of the effector molecules in apoptosis is Fas antigen . Crosslinking of Fas by its ligand (Fas L) or agonistic anti Fas antibodies induces apoptosis of cells expressing Fas on the membrane by triggering cascade of caspaces. The aim of this research was to study the percent of expression of Fas antigen on bone marrow and peripheral blood cells in 100 patients suffering from acute lymphoid and myeloid leukemia by flow cytometry method. Sample were obtained at the time of diagnosis before antileukemic therapy. Expression of Fas antigen on normal control peripheral leukocytes was also analysed. From these data, it was found that Fas antigen is expressed in all cases, but the expression level varied widely. The percentage of Fas antigen expression in all of acute lymphoid leukemia samples was below 20%, but in acute myeloid leukemia samples, 8 out of 50 cases was above 20%. In normal control samples, the mean value for monocytes was higher than granulocytes and in granulocytes higher than lymphcytes. Expression of Fas antigen in most of the leukemic cells was low and the preliminary results showed that increase in Fas antigen expression above 20% after treatment, is a favorable prognostic sign associated with increase relapse free and total survival. Thus evaluation of this antigen before, during and after treatment is recommended.
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PMID:Expression of Fas Antigen (CD95) on Human Leukemic Cells and Assessment of Apoptosis on Fas+ and Fas-Samples by Flowcytometry Method. 1730 82

Inducible hematopoietic stem/progenitor cell lines represent a model for studying genes involved in self-renewal and differentiation. Here, gene expression was studied in the inducible human CD34+ acute myelogenous leukemia cell line KG1 using oligonucleotide arrays and suppression subtractive cloning. Using this approach, we identified Dlg7, the homolog of the Drosophila Dlg1 tumor suppressor gene, as downregulated at the early stages of KG1 differentiation. Similarly, Dlg7 was expressed in normal purified umbilical cord blood CD34+CD38- progenitors but not in the more committed CD34+CD38+ population. Dlg7 expression was not detected in differentiated cells obtained from hematopoietic colonies, nor was expression detected in purified T-cells, B-cells, and monocytes. When analyzed in different types of stem cells, Dlg7 expression was detected in purified human bone marrow-derived CD133+ progenitor cells, human mesenchymal stem cells, and mouse embryonic stem (ES) cells. Overexpression of Dlg7 in mouse ES cells increased their growth rate and reduced the number of EBs emerging upon differentiation. In addition, the EBs were significantly smaller, indicating an inhibition in differentiation. This inhibition was further supported by higher expression of Bmp4, Oct4, Rex1, and Nanog in EBs overexpressing Dlg7 and lower expression of Brachyury. Finally, the Dlg7 protein was detected in liver and colon carcinoma tumors but not in normal adjacent tissues, suggesting a role for the gene in carcinogenesis. In conclusion, our results suggest that Dlg7 has a role in stem cell survival, in maintaining stem cell properties, and in carcinogenesis. Disclosure of potential conflicts of interest is found at the end of this article.
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PMID:Gene expression analysis of hematopoietic progenitor cells identifies Dlg7 as a potential stem cell gene. 1732 6

Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure disorder with cytopenia and a high propensity for myelodysplastic syndrome (MDS) and leukaemia, particularly acute myeloid leukaemia. The mechanism of leukaemogenesis in SDS is unknown. In accordance to the multi-hit theory of carcinogenesis, it is likely that several molecular and cellular hits occur before MDS/leukaemia become apparent. This study used oligonucleotide microarray to identify gene expression patterns, which were shown to be associated with leukaemogenesis, in marrow mononuclear cells of nine SDS patients without overt transformation compared to healthy controls. Among 154 known leukaemia-related genes, several oncogenes were found to be upregulated, including LARG, TAL1 and MLL, and of several tumour suppressor genes were downregulated, including DLEU1, RUNX1, FANCD2 and DKC1. Real time polymerase chain reaction confirmed statistically higher expression of LARG and TAL1 in SDS marrows. We conclude that SDS marrow mononuclear cells exhibit abnormal gene expression patterns, which might result in continuous stimulation favouring evolution or progression of malignant clones. Additional molecular and cytogenetic events are probably necessary for the malignant process to be irreversible and complete.
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PMID:Leukaemia-related gene expression in bone marrow cells from patients with the preleukaemic disorder Shwachman-Diamond syndrome. 1753 75

The Aurora kinases play an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Aberrant expression of these kinases occurs in solid tumors and is associated with aneuploidy and carcinogenesis. We found in this study that Aurora kinase A and B were aberrantly expressed in a variety of types of human leukemia cell lines (n = 15, e.g., PALL-1, PALL-2, HL-60, NB4, MV4-11, etc.), as well as freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n = 44) compared with bone marrow mononuclear cells from healthy volunteers (n = 11), as measured by real-time PCR. ZM447439 is a novel selective Aurora kinase inhibitor. The compound induced growth inhibition, caused accumulation of cells with 4N/8N DNA content, and mediated apoptosis of human leukemia cells as measured by thymidine uptake, cell cycle analysis, and annexin V staining, respectively. Especially profound growth inhibition occurred with the PALL-1 and PALL-2 cells, which possess wild-type p53 gene. In contrast, ZM447439 did not inhibit clonogenic growth of myeloid committed stem cells harvested from healthy normal volunteers. Taken together, inhibition of Aurora kinases may be a promising treatment strategy for individuals with leukemia.
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PMID:A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia. 1754 Oct 33

We have identified a novel fusion partner of MLL, namely the mastermind like 2 (MAML2 gene), in secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with inv(11)(q21q23). RT-PCR and sequencing revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the NH2-terminal part of MLL and 952 amino acids from the COOH-terminal part of MAML2. The NH2-terminal part of MAML2, a basic domain including a binding site of the intracellular domain of NOTCH, was deleted in MLL-MAML2. MLL-MAML2 in secondary AML/MDS and MECT1-MAML2 in mucoepithelioid carcinoma, benign Wartin's tumor, and clear cell hidradenoma consist of the same COOH-terminal part of MAML2. A luciferase assay revealed that MLL-MAML2 suppressed HES1 promoter activation by the NOTCH1 intracellular domain. MAML2 involving a chimeric gene might contribute to carcinogenesis in multiple neoplasms by the disruption of NOTCH signaling.
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PMID:Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23). 1755 48

Drugs that target DNA topoisomerase II (Top2), including etoposide (VP-16), doxorubicin, and mitoxantrone, are among the most effective anticancer drugs in clinical use. However, Top2-based chemotherapy has been associated with higher incidences of secondary malignancies, notably the development of acute myeloid leukemia in VP-16-treated patients. This association is suggestive of a link between carcinogenesis and Top2-mediated DNA damage. We show here that VP-16-induced carcinogenesis involves mainly the beta rather than the alpha isozyme of Top2. In a mouse skin carcinogenesis model, the incidence of VP-16-induced melanomas in the skin of 7,12-dimethylbenz[a]anthracene-treated mice is found to be significantly higher in TOP2beta(+) than in skin-specific top2beta-knockout mice. Furthermore, VP-16-induced DNA sequence rearrangements and double-strand breaks (DSBs) are found to be Top2beta-dependent and preventable by cotreatment with a proteasome inhibitor, suggesting the importance of proteasomal degradation of the Top2beta-DNA cleavage complexes in VP-16-induced DNA sequence rearrangements. VP-16 cytotoxicity in transformed cells expressing both Top2 isozymes is, however, found to be primarily Top2alpha-dependent. These results point to the importance of developing Top2alpha-specific anticancer drugs for effective chemotherapy without the development of treatment-related secondary malignancies.
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PMID:Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies. 1757 14

Methylation of DNA at 5-position of cytosine, catalyzed by DNA methyltransferases, is the predominant epigenetic modification in mammals. Aberrations in methylation play a causal role in a variety of diseases, including cancer. Recent studies have established that like mutation, methylation-mediated gene silencing often leads to tumorigenesis. Paradoxically, genome-wide DNA hypomethylation may also play a causal role in carcinogenesis by inducing chromosomal instability and spurious gene expression. Since methylation does not alter DNA base sequence, much attention has been focused recently on developing small molecule inhibitors of DNA methyltransferases that can potentially be used as anticancer agents. Vidaza (5-azacytidine), marketed by Pharmion (Boulder, CO, USA), was the first DNA methyltransferase inhibitor approved by the U.S. Food and Drug Administration (FDA) for chemotherapy against myelodysplastic syndrome (MDS), a heterogeneous bone marrow disorder. Recently MGI Pharma Inc. (Bloomington, MN, USA) got FDA approval to market Dacogen (5-aza-2'-deoxycytidine, or decitabine) for treating MDS patients. These drugs were used earlier against certain anemias to induce expression of fetal globin genes. Interest in clinical trials of these drugs as anticancer agents has been renewed only recently because of reversal of methylation-mediated silencing of critical genes in cancer. Clinical trials have shown that both drugs have therapeutic potential against leukemia such as MDS, acute myeloid leukemia, chronic myelogenous leukemia and chronic myelomonocytic leukemia. In contrast, their effectiveness with solid tumors appears to be less promising, which challenges researchers to develop inhibitors with more efficacy and less toxicity. The major hindrance of their usage as anticancer agents is their instability in vivo as well as the toxicity secondary to their excessive incorporation into DNA, which causes cell cycle arrest. Gene expression profiling in cancer cells revealed that antineoplastic property of these drugs is mediated through both methylation-dependent and -independent pathways. Recently, we have shown that treatment of cancer cells with these cytidine analogues also induces proteasomal degradation of DNA methyltransferase 1, the ubiquitously expressed enzyme upregulated in almost all cancer cells. Development of related stable drugs that can facilitate gene activation in cancer cells by enhancing degradation of DNA methyltransferases without being incorporated into DNA would be ideal for chemotherapy. In this monograph we review historical perspective and recent advances on the molecular mechanisms of action and clinical applications of these DNA hypomethylating agents.
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PMID:DNA methyltransferases as targets for cancer therapy. 1761 10


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