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)

Tsg101 is a mouse tumor suppressor gene whose homozygous deletion produces transformation of NIH3T3 cells and leads to metastases in nude mice. The human homologue of the gene, TSG101, is localized in chromosome 11p15.1-p15.2. Reduced TSG101 expression may cause the defect of the cell cycle checkpoint that leads to genetic instability and consequently to the progression of neoplasia. Aberrant TSG101 transcript have been identified in many types of cancers, and the relaxation of RNA splicing fidelity may be an onco-developmental marker in cancers and could play a general role in tumorigenesis. In our previous study, smaller TSG101 transcripts were found in AML specimens, hematopoietic cell lines and normal controls. The aberrant transcripts occurred more frequently in the AML cases and cell lines. The patients with aberrant TSG101 transcripts had higher initial white cell count, lower LDH level, and lower complete remission rate after induction chemotherapy. However, further multivariate analysis of clinical data revealed that there was no relationship to the TSG101 aberrant transcripts. The clinical significance of TSG101 aberrant transcript in AML needs further evaluation.
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PMID:Clinical implications of aberrant TSG101 transcripts in acute myeloblastic leukemia. 1078 90

The Bcl10 gene was identified through characterization of the t(1;14)(p22;q32) associated with mucosa-associated lymphoid tissue (MALT) lymphoma. Bcl10 is implicated in the regulation of apoptosis and has been reported to be mutated in other subtypes of non-Hodgkin's B-cell lymphoma (B-NHL) and leukaemic cell lines, raising the possibility that its deregulation could be implicated in other forms of haematological malignancy. We screened 226 cases, including 123 acute myeloid leukaemia (AML), 50 acute lymphoblastic leukaemia (ALL), 20 chronic myeloid leukaemia (CML), 10 chronic lymphocytic leukaemia-prolymphocytic leukaemia (CLL/PLL) and 23 cases with 1p abnormalities, for Bcl10 mutations by reverse transcription polymerase chain reaction-single-stranded conformation polymorphism (RT-PCR/SSCP). Three known polymorphisms and two common splice variants were identified; however, no mutations were detected. One splice variant led to a 33-bp in frame deletion, whereas the other caused a 16-bp deletion predicting C-terminal truncation of Bcl10. However, both splice variants were also detected in normal bone marrow, suggesting that they are unlikely to be of pathogenetic significance. Furthermore, Southern blot analysis revealed no rearrangements of Bcl10 among 16 ALL and 11 cases of haematological malignancy with 1p abnormalities. Our results suggest that mutation of the Bcl10 gene as a mechanism of tumorigenesis is not associated with leukaemia.
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PMID:Screening for mutations of Bcl10 in leukaemia. 1088 11

Acute myeloid leukemia (AML) is a heterogeneous group of diseases. Normal cytogenetics (CN) constitutes the single largest group, while trisomy 8 (+8) as a sole abnormality is the most frequent trisomy. How trisomy contributes to tumorigenesis is unknown. We used oligonucleotide-based DNA microarrays to study global gene expression in AML+8 patients with +8 as the sole chromosomal abnormality and AML-CN patients. CD34(+) cells purified from normal bone marrow (BM) were also analyzed as a representative heterogeneous population of stem and progenitor cells. Expression patterns of AML patients were clearly distinct from those of CD34(+) cells of normal individuals. We show that AML+8 blasts overexpress genes on chromosome 8, estimated at 32% on average, suggesting gene-dosage effects underlying AML+8. Systematic analysis by cellular function indicated up-regulation of genes involved in cell adhesion in both groups of AML compared with CD34(+) blasts from normal individuals. Perhaps most interestingly, apoptosis-regulating genes were significantly down-regulated in AML+8 compared with AML-CN. We conclude that the clinical and cytogenetic heterogeneity of AML is due to fundamental biological differences.
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PMID:Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics. 1115 5

Two distinct clinical syndromes have been associated with the p11.12 region of the short arm of chromosome 8: stem-cell myeloproliferative disorder (B-or T-cell lymphoblastic leukemia/lymphoma with myeloid hyperplasia and peripheral blood eosinophilia) and acute myeloid leukemia (myelomonocytic or monocytic with erythrophagocytosis). The FGFR1 and MOZ genes are rearranged in these diseases and encode one of the four fibroblast growth factor receptors and a member of a novel histone acetyltransferase family, respectively. The predicted fusion proteins that are putatively oncogenic - FOP-FGFR1, CEP110-FGFR1, and FIM-FGFR1 - and - MOZ-CBP, MOZ-p300, and MOZ-TIF2 - lead to tumorigenesis through distinct pathways. The constitutive kinase activity triggered by dimerization mediated by the protein-protein interaction motifs of the FGFR1 protein partner regardless of external stimuli and the delocalization of the fusion proteins compared to their normal counterparts may lead to tumorigenesis presumably by inducing inappropriate recruitment in the cytoplasm of signaling substrates. Currently, little is known about the precise role of MOZ in the regulation of gene transcription. However, all the aberrant proteins described to date retain the MOZ histone acetyltransferase domain fused to that of the transcription coactivators CBP, p300, and TIF2. The fusion of two acetyltransferases whose activity may be mistargetted or misregulated could be a critical event in leukemogenesis. The increasing number of translocations affecting FGFR1 and MOZ strongly suggest their involvement in oncogenic processes and point to these proteins as potential therapeutical targets.
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PMID:[FGFR1 and MOZ, two key genes involved in malignant hemopathies linked to rearrangements within the chromosomal region 8p11-12]. 1117 18

Aberrant DNA methylation is believed to be important in tumorigenesis by causing either transcriptional inactivation of genes or chromosomal instability. Several laboratories have identified promoter hypermethylation of tumor suppressor genes in acute myeloid leukemia (AML). However, these studies do not provide a global assessment of overall methylation changes and do not allow the identification of novel methylated sequences. Previously, nonrandom CpG island methylation was reported in 17 adult de novo AML diagnostic samples when compared with the corresponding remission samples by means of restriction landmark genomic scanning (RLGS). That study has been expanded on by an analysis of a larger set of CpG islands (1740 vs 1184), which now provides details of 33 cloned methylated loci, including 21 known genes or expressed sequence tags. Five of these cloned loci appear to be methylated only in AML and not in the 6 solid tumors studied in this study (more than 98 samples analyzed). Chromosomal location was available for 30 of the 33 loci, and 5 of these 30 (17%) are localized to chromosome 11, suggesting a trend toward overrepresentation of methylation events on this chromosome. These results provide evidence for widespread aberrant methylation in AML, with identification of novel methylation targets, epigenetic changes that appear unique to AML, and apparent preferential methylation on chromosome 11.
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PMID:Novel methylation targets in de novo acute myeloid leukemia with prevalence of chromosome 11 loci. 1134 53

There is increasing interest in changing the emphasis of tumor classification from morphologic to molecular. Gene expression profiles may offer more information than morphology and provide an alternative to morphology-based tumor classification systems. Gene selection involves a search for gene subsets that are able to discriminate tumor tissue from normal tissue, and may have either clear biological interpretation or some implication in the molecular mechanism of the tumorigenesis. Gene selection is a fundamental issue in gene expression-based tumor classification. In the formation of a discriminant rule, the number of genes is large relative to the number of tissue samples. Too many genes can harm the performance of the tumor classification system and increase the cost as well. In this report, we discuss criteria and illustrate techniques for reducing the number of genes and selecting an optimal (or near optimal) subset of genes from an initial set of genes for tumor classification. The practical advantages of gene selection over other methods of reducing the dimensionality (e.g., principal components), include its simplicity, future cost savings, and higher likelihood of being adopted in a clinical setting. We analyze the expression profiles of 2000 genes in 22 normal and 40 colon tumor tissues, 5776 sequences in 14 human mammary epithelial cells and 13 breast tumors, and 6817 genes in 47 acute lymphoblastic leukemia and 25 acute myeloid leukemia samples. Through these three examples, we show that using 2 or 3 genes can achieve more than 90% accuracy of classification. This result implies that after initial investigation of tumor classification using microarrays, a small number of selected genes may be used as biomarkers for tumor classification, or may have some relevance in tumor development and serve as a potential drug target. In this report we also show that stepwise Fisher's linear discriminant function is a practicable method for gene expression-based tumor classification.
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PMID:Feature (gene) selection in gene expression-based tumor classification. 1146 Nov 91

The mts1/S100A4 gene encodes a small acidic calcium-binding protein that is expressed in a cell-specific manner in development, tumorigenesis and certain tissues of adult mice. A composite enhancer that is active in murine mammary adenocarcinoma cells was previously identified in the first intron of the mts1/S100A4 gene. Here we present a detailed analysis of the structure and function of this enhancer in the Mts1/S100A4-expressing CSML100 and non-expressing CSML0 mouse adenocarcinoma cell lines. In CSML100 cells the enhancer activity is composed of at least six cis-elements interacting with Sp1 and AP-1 family members and CBF/AML/PEBP2 and KRC transcription factors. In addition, a minisatellite-like DNA sequence significantly contributes to the enhancer activity via interaction with abundant proteins, which likely have been described previously under the name minisatellite-binding proteins. Extensive mutational analysis of the mts1/S100A4 enhancer revealed a cooperative function of KRC and the factors binding minisatellite DNA. This is the first example of an enhancer where two nuclear factors earlier implicated in different recombination processes cooperate to activate transcription. In Mts1/S100A4-negative CSML0 cells the strength of the enhancer was 7- to 12.5-fold lower compared to that in CSML100 cells, when referred to the activities of three viral promoters. In CSML0 cells the enhancer could be activated by exogenous AP-1 and CBF transcription factors.
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PMID:Characterization of Sp1, AP-1, CBF and KRC binding sites and minisatellite DNA as functional elements of the metastasis-associated mts1/S100A4 gene intronic enhancer. 1150 71

We describe here the development of a murine system for the identification of genes involved in myelomonocytic neoplasms. Transgenic C57BL/6J mice expressing SV40 early region under a myelomonocytic promoter develop histiocytic sarcomas with a latency of 167 days. We used retroviral proviral tagging to accelerate tumorigenesis and to uncover genetic changes that contribute to tumor development. Infection of transgenic mice with Friend murine leukemia virus (F-MuLV) shortened the latency of morbidity to 103 days (P< 0.001); this was associated with clonal proviral integrations in tumor DNA. As expected for F-MuLV, proviral insertions occurred at Fli1 in both transgenic and nontransgenic tumors. Four insertions were found at a novel locus, termed Fim4, on chromosome 6. This region is syntenic to human 7q32, a region that is commonly deleted in human myelodysplastic syndrome and acute myeloid leukemia. A murine BAC containing Fim4 was sequenced and analyzed, and while there was significant human-mouse homology in the area of the insertions, no candidate gene has been identified. Thus we have established a system to identify genes involved in myelomonocytic tumors, and have used it to identify Fim4, a new common site of proviral insertion. Study of this locus may provide insight into genes involved in AML-associated 7q32 deletions in humans.
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PMID:F-MuLV acceleration of myelomonocytic tumorigenesis in SV40 large T antigen transgenic mice is accompanied by retroviral insertion at Fli1 and a novel locus, Fim4. 1220 Jun 99

We have used the single and dual color fluorescence in situ hybridization (FISH) technique combined with a new detection system, tyramide signal amplification (TSA), by using the multiple endocrine neoplasm type 1 (MEN1) gene and chromosome 11 specific alpha satellite DNA probes for the study of the allelic deletion of the MEN1 gene. The MEN1 gene is a new tumor suppressor gene and has been recently cloned on chromosome 11q13. FISH combined with the TSA detection system was performed on bone marrow interphase nuclei of 22 patients with acute myeloid leukemia (AML). The FISH-TSA analysis revealed the mono allelic deletion of the MEN1 gene in 4 out of 22 patients (18.18%), 2 of 9 AML-M2 patients (22.2%), 1 of 6 AML-M4 patients (16.6%), and 1 of 4 AML-M5 patients (25.0%). Our study indicates that allelic deletion of the MEN1 gene is not a major cause or a primary event in tumorigenesis of AML, although the long arm (q13 region) of chromosome 11 involves a chromosomal rearrangement in AML.
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PMID:Determination of allelic deletion of multiple endocrine neoplasm type 1 (MEN1) gene in acute myeloid leukemia (AML) by application of FISH-TSA technique. 1221 May

Fusions of the TET-proteins (TLS/FUS, EWSR1, and TAF15/RBP56) to different transcription factors are involved in various malignancies including Ewing's sarcoma, primitive neuroectodermal tumors, and acute myeloid leukemia. These are thought to arise through transcriptional deregulation, with the transcription factor defining the tumor phenotype. We show that, as result of a t(12;17)(p13;q11) or its variant t(12;22)(p13;q12), the transcription factor gene CIZ/NMP4 is recurrently involved in acute leukemia through fusion with either EWSR1 or TAF15. The fusions possess transforming properties in NIH3T3 cells but do not affect the expression of CIZ target genes, suggesting a contribution to oncogenesis that is independent of the transactivating properties of the fusion protein. These results also extend the involvement of TET-protein fusions to acute lymphoblastic leukemia and suggest a role for CIZ/NMP4 in lymphoid and myeloid development.
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PMID:Recurrent rearrangement of the Ewing's sarcoma gene, EWSR1, or its homologue, TAF15, with the transcription factor CIZ/NMP4 in acute leukemia. 1235 45


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