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

Normal cell development and function is dependent upon controlled gene expression. DNA methylation is an epigenetic modification that can play an important role in the control of gene expression. DNA methylation at cytosine residues in gene promoter CpG sequences is known to inhibit gene transcription. Inappropriate inhibition of the transcription of tumour suppressor genes, genes that inhibit angiogenesis and metastasis and genes involved in DNA repair by uncontrolled methylation, can lead to unregulated growth and proliferation of a cell and carcinogenesis. Promoter hypermethylation affecting the p16 gene, resulting in gene silencing, has been shown to occur in many human solid tumours and a 'hypermethylation profile' in some leukaemias has been defined. The molecular mechanisms by which aberrant DNA methylation takes place during carcinogenesis are still not clear. However, the large number of target genes (involved in tumorigenesis) that are silenced by aberrant methylation suggests that inhibition of this process may have potential as cancer therapy. Decitabine (NSC-127716, Dacogen; SuperGen) is a potent and specific hypomethylating agent and an inhibitor of the DNA methyltransferase activity that mediates DNA methylation. Decitabine has been shown to have a broad range of antineoplastic activity in preclinical studies. This agent has exhibited significant activity in the treatment of patients with myelodysplastic syndrome, chronic myeloid leukaemia and acute myeloid leukaemia, although clinical Phase I and II studies with solid tumours have not been very promising. Phase II and III studies are currently ongoing to evaluate decitabine, both alone and in combination, in various stages of these haematological malignancies.
 ...
PMID:DNA methylation in haematological malignancies: the role of decitabine. 1464 Sep 42

Human tumor cell lines are powerful tools for investigating basic and applied aspects of cell biology. Leukemia-lymphoma cell lines have been instrumental in the cytogenetic and molecular analysis of recurring chromosome rearrangements, notably translocations and inversions, thus illuminating the pathogenesis of hematological malignancy. Chromosomal translocations targeting the MLL gene at 11q23 have come to represent a paradigm in acute leukemias. These translocations result in the in-frame joining of the MLL gene with a partner gene to generate unique fusion proteins of putatively novel function. More than 30 partner genes that participate with MLL in the more than 60 known 11q23 translocations have been reported. Cell lines provide territory to both explore the detailed structures of 11q23 translocations and investigate the leukemogenic activities of MLL fusion proteins. We review here the leukemia cell lines that have been described to carry 11q23 translocations and MLL fusion genes. Except for the t(10;11)(p12;q23), each of the following relatively frequent 11q23/MLL translocations is represented by one or more cell lines: 16 cell lines with t(4;11)(q21;q23), two cell lines with t(6;11)(q27;q23), seven cell lines with t(9;11)(p22;q23), and eight cell lines with t(11;19)(q23;p13). For each of three rare translocations, one cell line has been reported: t(5;11)(q15;q23), t(11;16)(q23;p13), and t(X;11)(q13;q23). Of these 36 cell lines with 11q23 translocations, 17 have been made available to us; we confirmed the occurrence of the alterations reported in these cell lines at the chromosomal and/or gene level. A second type of MLL gene alteration is the partial tandem duplication (PTD), which occurs in acute myeloid leukemia (AML). We found four AML cell lines with an MLL PTD; one acute lymphoblastic leukemia-derived cell line was reported to show a partial nontandem duplication. Finally, a third rearrangement involves intrachromosomal amplification of the unrearranged MLL gene leading to multiple copies of the gene and (presumably) increased expression. Three cell lines carrying such MLL amplifications have been described. The availability of these cell lines as model systems provides the opportunity to explore the altered expression or functions of MLL genes and their partners in oncogenesis.
 ...
PMID:Malignant hematopoietic cell lines: in vitro models for the study of MLL gene alterations. 1467 38

Centrosomes, which mediate accurate chromosome segregation during mitosis, undergo duplication precisely once per cell division at the G1/S boundary. Recently, we described centrosome aberrations as a possible cause of aneuploidy in acute myeloid leukemia (AML) and found a correlation of the percentage of cells carrying abnormal centrosomes to their cytogenetic risk profile. To elucidate the molecular events responsible for the development of centrosome aberrations in AML, tumor RNA of 29 AML samples was hybridized to cDNA microarrays. The microarrays comprised some 2800 different genes with relevance to hematopoiesis, tumorigenesis and mitosis and included a set of 359 centrosome-associated genes. We identified two gene expression signatures, which allowed an accurate classification according to the extent of centrosome aberrations and the ploidy status in 28 of 29 patients each. Specifically, 18 genes were present in both signatures, including genes that code for cell cycle regulatory proteins (cyclin A2, cyclin D3, cyclin H, CDK6, p18INK4c, p21Cip1, PAK1) and centrosome-associated proteins (pericentrin, alpha2-tubulin, NUMA1, TUBGCP2, PRKAR2A). In conclusion, the high expression of centrosome-associated genes matches the description of centrosome aberrations in several tumor types. Moreover, in AML the identification of G1/S-phase stimulatory genes suggests that one mechanism of aneuploidy induction might be the deregulation of centrosome replication at the G1/S boundary.
 ...
PMID:Gene expression patterns in acute myeloid leukemia correlate with centrosome aberrations and numerical chromosome changes. 1476 74

Since their original identification in Drosophila, the caudal related homologues (Cdx1 and Cdx2) have been known to be evolutionarily conserved both in molecular structure and function. In a great variety of organisms they are recognized to function critically during antero-posterior patterning and the development of the intestinal epithelium. The Cdx homologues, when expressed, modulate a diverse set of processes including proliferation, apoptosis, cell-adhesion, and columnar morphology. They are also necessary for the expression of an increasing number of intestine-specific genes. By targeting these processes and genes, the Cdx homologues promote the appearance of a mature intestinal cell phenotype. In addition to these critical roles during development, accumulating evidence suggests that the Cdx homologues may play significant roles in oncogenesis in the gastrointestinal tract and other tissues. In the colon, several studies suggest the Cdx homologues may act as tumor suppressors. However, ectopic Cdx1 and Cdx2 expression is involved in the development of the precancerous intestinal metaplasia in the stomach and esophagus, and may be a transforming event in one form of acute myelogenous leukemia. This review will explore our current understanding of the roles of the caudal homologues Cdx1 and Cdx2 in intestinal development and carcinogenesis.
 ...
PMID:The role of Cdx proteins in intestinal development and cancer. 1513 61

The detection of chromosomal aberrations is essential for the diagnosis and therapy of acute myeloid leukaemia (AML). We report two cases of de novo AML with translocations involving the breakpoint 6p22 first detected at relapse. Chromosomes were identified by conventional and molecular cytogenetics. At diagnosis, one patient presented a normal karyotype and the other one a trisomy 11 and a del(7)(q31q36). In the first case, cytogenetic analyses at relapse revealed a t(3;6)(q21;p22). The second patient showed a t(1;6)(q21;p22) at relapse. Detailed characterization of the breakpoints on the short arm of chromosome 6 was performed using array comparative genomic hybridization (CGH) on a platform specific for chromosome 6. In both cases, array CGH showed a terminal deletion and a small internal duplication of the short arm of chromosome 6. The region 6p22 is involved in several aberrations in tumours. Translocation partners are distributed throughout the human genome. We identified 3q21, a recurrent breakpoint in AML, for the first time as a translocation partner. The fragile site FRA6C, located in 6p22.2, and possibly the genes that reside within it, may play a role in tumorigenesis. The occurrence of translocations involving 6p22 after chemotherapy or radiation therapy suggests that one or more therapeutic agents might play a role in their origin.
 ...
PMID:Translocations involving 6p22 in acute myeloid leukaemia at relapse: breakpoint characterization using microarray-based comparative genomic hybridization. 1528 41

The putative tumour suppressor gene gravin is down-regulated in several solid tumours and is implicated in tumorigenesis. We have evaluated the expression levels of the gravin gene in the CD34(+)/blast cells of a range of myeloid malignancies as compared with controls using real-time quantitative polymerase chain reaction (PCR). Gravin was markedly down-regulated in 41 of 41 patients with acute myeloid leukaemia (AML), nine of 10 patients with myelodysplastic syndromes (MDS) and 33 of 33 patients with chronic myeloid leukaemia (CML), of whom 24 were in blast crisis (BC). We have shown that gravin is consistently down-regulated in the CD34(+)/blast cells of myeloid malignancies and may play a role in the molecular pathogenesis of these disorders.
 ...
PMID:Low expression of the putative tumour suppressor gene gravin in chronic myeloid leukaemia, myelodysplastic syndromes and acute myeloid leukaemia. 1528 43

Telomere length and telomerase have an important role in normal and malignant hematopoiesis. Telomere erosion can lead to chromosome end fusion and thereby contribute to genomic instability during tumorigenesis. Thus, like complex chromosomal aberrations, telomere length may be a prognostic factor in hematopoietic malignancies. A paper by Sieglova et al. in this issue of Leukemia Research reports on the prognostic impact of telomere shortening in bone marrow (BM) and peripheral blood (PB) specimens of myelodysplastic syndrome (MDS) and MDS converted-AML patients (pts). Their results underline the importance to study telomere biology together with cytogenetics, genomic and proteomic profiling as prognostic factors, in order to improve risk-adapted therapy of MDS and AML pts.
 ...
PMID:Telomeres and telomerase in normal and leukemic hematopoietic cells. 1528 12

Normal blood-cell differentiation is controlled by regulated gene expression and signal transduction. Transcription deregulation due to chromosomal translocation is a common theme in hematopoietic neoplasms. AML1-ETO, which is a fusion protein generated by the 8;21 translocation that is commonly associated with the development of acute myeloid leukemia, fuses the AML1 runx family DNA-binding transcription factor to the ETO corepressor that associates with histone deacetylase complexes. Analyses have demonstrated that AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. Here, we report that the loss of the molecular events of AML1-ETO C-terminal NCoR/SMRT-interacting domain transforms AML1-ETO into a potent leukemogenic protein. Contrary to full-length AML1-ETO, the truncated form promotes in vitro growth and does not obstruct the cell-cycle machinery. These observations suggest a previously uncharacterized mechanism of tumorigenesis, in which secondary mutation(s) in molecular events disrupting the function of a domain of the oncogene promote the development of malignancy.
 ...
PMID:Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. 1557 47

Endometrial carcinoma is the most common gynecological malignant disease in industrialized countries. Two clinicopathological types of endometrial carcinoma have been described, based on estrogen relation and grade: endometrioid carcinoma (EEC) and non-EEC (NEEC). Some of the molecular events that occur during the development of endometrial carcinoma have been characterized, showing a dualistic genetic model for EEC and NEEC. However, the molecular bases for endometrial tumorigenesis are not clearly elucidated. In the present work, we attempted to identify new genes that could trigger cell transformation in EEC. We analyzed the differential gene expression profile between tumoral and nontumoral endometrial specimens with cDNA array hybridization. Among the 53 genes for which expression was found to be altered in EEC, the acute myeloid leukemia proto-oncogene, RUNX1/AML1, was one of the most highly up-regulated. The gene expression levels of RUNX1/AML1 were quantified by real-time quantitative PCR, and protein levels were characterized by tissue array immunohistochemistry. Real-time quantitative PCR validated RUNX1/AML1 up-regulation in EEC and demonstrated a specific and significantly stronger up-regulation in those tumor stages associated with myometrial invasion. Furthermore, tissue array immunohistochemistry showed that RUNX1/AML1 up-regulation correlates to the process of tumorigenesis, from normal atrophic endometrium to simple and complex hyperplasia and then, on to carcinoma. These results demonstrate for the first time the up-regulation of RUNX1/AML1 in EEC correlating with the initial steps of myometrial infiltration.
 ...
PMID:A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma. 1560 43

H19 and IGF-2 are two growth regulatory genes located on chromosome 11p15 implicated in tumorigenesis. Both genes are imprinted and regulated reciprocally under many circumstances. In order to elucidate the contribution of H19 and IGF-2 to leukemogenesis, the mRNA expression level of both genes were quantitated in bone marrow biopsies and peripheral blood samples from normal (n=98), chronic myelomonocytic leukemia (CMML, n=43), chronic myelogenous leukemia (CML, n=40) and, acute myelogenous leukemia (AML, n=32) cases. A concomitant reduction of H19 and IGF-2 expression was observed in all leukemic samples compared to the healthy controls. This down-regulation was not accompanied by changes in methylation of the differentially methylated region (DMR). Whereas the H19 gene showed strict monoallelic expression in all informative normal (n=31) and leukemic (n=54) samples, the imprinting pattern of the IGF2 gene was found to be heterogeneous. No correlations between imprinting status (mono- versus biallelic expression), quantitative mRNA expression levels and course of disease were found for the IGF-2 gene. The data suggest a disturbed regulation of the IGF-2/H19 locus in myeloid leukemias which is not caused by loss of imprinting.
 ...
PMID:Down-regulation of the IGF-2/H19 locus during normal and malignant hematopoiesis is independent of the imprinting pattern. 1564 36


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>