Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) translocations associated with myelogenous leukemias and encodes a DNA binding protein. From the AML1 gene, two representative forms of proteins, AML1a and AML1b, are produced by alternative splicing. Both forms have a DNA binding domain but, unlike AML1b, AML1a lacks a putative transcriptional activation domain. Here we demonstrate that overexpressed AML1a totally suppresses granulocytic differentiation and stimulates cell proliferation in 32Dcl3 murine myeloid cells treated with granulocyte colony-stimulating factor. These effects of AML1a were canceled by the concomitant overexpression of AML1b. Such biological phenomena could be explained by our observations that (i) AML1a, which on its own has no effects as a transcriptional regulator, dominantly suppresses transcriptional activation by AML1b, and (ii) AML1a exhibits the higher affinity for DNA binding compared with AML1b. These antagonistic actions could be important in leukemogenesis and/or myeloid cell differentiation because more than half of myelogenous leukemia patients showed an increase in the relative amounts of AML1a.
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PMID:An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms. 753 Jun 57

The t(8;21) translocation is one of the most frequent chromosome abnormalities in acute myeloid leukemia. It has been shown that the t(8;21) breakpoints on chromosome 21 cluster within a single specific intron of the AML1 gene, which is highly homologous to the Drosophila segmentation gene runt. Here we report that this translocation juxtaposes the AML1 gene with a novel gene, named MTG8, on chromosome 8, resulting in the synthesis of an AML1-MTG8 fusion transcript. The fusion protein predicted by the AML1-MTG8 transcript consists of the runt homology region of AML1 and the most part of MTG8, which contains putative zinc finger DNA binding motifs and proline-rich regions constituting a characteristic feature of transcription factors. The MTG8 gene is not expressed in normal hematopoietic cells, whereas AML1 is expressed at high levels. Our results indicate that the production of chimeric AML1-MTG8 protein, probably a chimeric transcription factor, may contribute to myeloid leukemogenesis.
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PMID:The t(8;21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript. 833 90

Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.
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PMID:Duplication and loss of chromosome 21 in two children with Down syndrome and acute leukemia. 858 82

A short review of chromosome 21 abnormalities in acute lymphoblastic leukemia (ALL) is presented. Trisomy and polysomy 21 are nonrandom anomalies that are frequently observed in ALL. Their occurrence, although not specific, as well as the high incidence of acute leukemia in subjects with constitutional trisomy 21, suggests that chromosome 21 plays a particular role in leukemogenesis. More specific to ALL, t(12;21)(p13;q22), resulting in a fusion TEL-AML1, gene has recently been shown to be the most frequent translocation in childhood B-cell lineage ALL (20-30% of cases). In addition, the importance of analysis of marker chromosomes with fluorescence in situ hybridization (FISH) techniques is underscored as partial amplifications or rearrangements of chromosome 21 may be implicated.
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PMID:Acute lymphoblastic leukemia and chromosome 21. 907 85

Impressive gains have been made in the therapy of childhood acute lymphoblastic leukemia (ALL) in recent years such that remissions today are commonly achieved in up to 95% of patients and long term disease-free survival rates approach 70%. Methotrexate is a key component in ALL consolidation and maintenance therapies and is administered intrathecally in the prophylaxis and treatment of central nervous system leukemia. Critical determinants of methotrexate sensitivity and resistance (dihydrofolate reductase levels, methotrexate membrane transport, methotrexate polyglutamylation) previously described in cultured cells have recently been identified in lymphoblasts from children with ALL. Heterogenous expressions of increased dihydrofolate reductase or impaired methotrexate transport can be detected in both diagnostic and relapsed ALL specimens by flow cytometry with fluorescent methotrexate analogues. Lymphoblasts from children with ALL synthesize long chain polyglutamates and correlations have been established between the accumulation of methotrexate polyglutamates in ALL blasts and characteristic patient prognostic features. Variations in methotrexate polyglutamate accumulation may reflect changes in polyglutamate synthetic or degradative enzymes, or may be secondary to changes in methotrexate influx or dihydrofolate reductase levels. Other critical elements in treatment response to methotrexate include the dose and route of methotrexate administration, its catabolism to 7-hydroxymethotrexate, and the rate of methotrexate plasma clearance. A unique relationship exists between chromosome 21 and ALL leukemogenesis, and response to treatment including methotrexate. A better understanding of the molecular bases of methotrexate response and the development of methotrexate resistance in childhood ALL should facilitate further improvements in the effectiveness of methotrexate-based chemotherapy for this disease.
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PMID:Methotrexate pharmacology and resistance in childhood acute lymphoblastic leukemia. 917

The (8;21)(q22;q22) translocation, reported in 40% of M2-subtype acute myeloid leukemias (AMLs), is the second-most frequently observed example of a nonrandom genetic alteration associated with AML. Juxtaposition of the AML1 gene on chromosome 21 to the ETO gene on chromosome 8 fuses the NH2-terminal portion of AML1 to near-full length ETO, creating AML1/ETO. Previous work has been focused on perturbation of AML1 gene function by the chimeric fusion protein as a mechanism of leukemogenesis. Here, we demonstrate that ETO itself has transforming properties. Ectopic ETO expression in NIH/3T3 cells led to foci of transformation and colony growth in soft agar. ETO-expressing cells grew to higher saturation densities and induced tumors following injection into irradiated and splenectomized nude mice. Our data suggests that ETO may play an important role in the leukemic transforming potential of the AML1/ETO fusion protein.
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PMID:Transformation properties of the ETO gene, fusion partner in t(8:21) leukemias. 923 Feb 7

AML1, a gene on chromosome 21 encoding a transcription factor, is disrupted in the (8;21)(q22;q22) and (3;21)(q26;q22) chromosomal translocations associated with myelogenous leukemias; as a result, chimeric proteins AML1/ETO(MTG8) and AML1/Evi-1 are generated, respectively. To clarify the roles of AML1/ETO(MTG8) and AML1/Evi-1 in leukemogenesis, we investigated subcellular localization of these chimeric proteins by immunofluorescence labeling and subcellular fractionation of COS-7 cells that express these chimeric proteins. AML1/ETO(MTG8) and AML1/Evi-1 are nuclear proteins, as is wild-type AML1. Polyomavirus enhancer binding protein (PEBP)2beta(core binding factor [CBF]beta), a heterodimerizing partner of AML1 that is located mainly in the cytoplasm, was translocated into the nucleus with dependence on the runt domain of AML1/ETO(MTG8) or AML1/Evi-1 when coexpressed with these chimeric proteins. When a comparable amount of wild-type AML1 or the chimeric proteins was coexpressed with PEBP2beta(CBFbeta), more of the cells expressing the chimeric proteins showed the nuclear accumulation of PEBP2beta(CBFbeta), as compared with the cells expressing wild-type AML1. We also showed that the chimeric proteins associate with PEBP2beta(CBFbeta) more effectively than wild-type AML1. These data suggest that the chimeric proteins are able to accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1, probably because of the higher affinities of the chimeric proteins for PEBP2beta(CBFbeta) than that of wild-type AML1. These effects of the chimeric proteins on the cellular distribution of PEBP2beta(CBFbeta) possibly cause the dominant negative properties of the chimeric proteins over wild-type AML1 and account for one of the mechanisms through which these chimeric proteins contribute to leukemogenesis.
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PMID:The AML1/ETO(MTG8) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1. 947 35

Chromosomal translocations involving the human 12p13 band frequently affect the TEL gene, usually resulting in gene fusion between TEL and genes encoding proteins of various types. The most frequent 12p13 translocation is the t(12;21)(p13;q22), which recombines TEL with the AML1 gene on chromosome 21 and is frequently associated with deletion of the untranslocated TEL allele. Using antisera against different parts of TEL and against the AML1 proteins, we undertook Western blot and immunofluorescence analyses of leukemic samples with and without 12p13 abnormalities. In t(12;21) samples, TEL-AML1 was detected as several protein species in the nuclei, whereas the AML1-TEL protein, was inconsistently expressed. AML1 was found to be expressed but no normal TEL proteins were detected. A survey of the TEL proteins in a panel of human leukemic samples without t(12;21) revealed a variation in the ratio of TEL protein isoforms. We also analysed a leukemic cell line bearing a t(12;22)(p13;q11) that was found to affect the 5' untranslated (UT) region of TEL and to be associated with inactivation of the untranslocated TEL allele. No MN1-TEL fusion could be detected upon RT-PCR analysis, in contrast to the previously investigated t(12;22). Strikingly, extremely low levels of apparently normal TEL proteins, expressed from the translocated allele, were detected by Western blot analysis. These results suggest that the level of TEL expression can be important for leukemogenesis.
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PMID:Analysis of TEL proteins in human leukemias. 967 10

Children with Down syndrome (DS) have a 10-20-fold increased risk of acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), compared to non-DS children. The myeloid leukemia that accounts for nearly 50% of DS leukemias is usually the otherwise uncommon megakaryoblastic type (AML-M7). Though an etiological role of trisomy 21 in leukemogenesis has been suggested, the expression of genes on chromosome 21 in relation to trisomy, DS, and specific DS phenotypes such as leukemia is poorly understood. We used a heterologous-mimic competitive RT-PCR technique to measure the mRNA levels of a chromosome 21 tumour invasion and metastasis factor (TIAM1) directly in bone marrow samples of DS leukemic patients. In the limited number of cases analysed so far, we found TIAM1 mRNA levels in the DS AML-M7 samples of bone marrow taken in the acute phase of the disease (presentation or relapse, n=8) to be highly significantly raised, nearly threefold, compared to that measured in the remission samples or normal individuals (normals + remissions, n=10).
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PMID:Increased levels of a chromosome 21-encoded tumour invasion and metastasis factor (TIAM1) mRNA in bone marrow of Down syndrome children during the acute phase of AML(M7). 971 98

The reciprocal translocation t(8;21)(q22;q22) is one of the most frequent chromosomal aberrations in acute myeloblastic leukemia (AML). At the molecular level, this aberration rearranges the gene for the AML1-transcription factor on chromosome 21, which is essential for normal hematopoiesis, to the MTG8 gene on chromosome 8, thereby leading to a specific AML1/MTG8 fusion mRNA. This fusion gene is involved in leukemogenesis presumably by interfering with normal AML1-dependent transcriptional regulation. AML patients with t(8;21) have a favourable response to chemotherapy and a relatively good prognosis after intensive consolidation treatment with high dose AraC or autologous stem cell transplantation. RT-PCR for the specific AML1/MTG8 fusion transcripts can be used for the sensitive detection of residual leukemic cells during and after therapy. However, since a considerable proportion of these patients shows a positive PCR result even in long-term complete hematological remission, the prognostic value of qualitative PCR methods is doubtful. In contrast, quantitative PCR methods might be able to identify patients with a high risk of relapse by serial quantification of minimal residual disease (MRD). Because of its high degree of standardisation and automation, the recently developed real time PCR method can be used for the valid and reproducible detection of MRD in large prospective trials. This technology offers the potential to define the antileukemic efficiency of different treatment elements and the prognostic value of MRD in patients with t(8;21) positive AML.
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PMID:The AML1/MTG8 Fusion Transcript in t(8;21) Positive AML and its Implication for the Detection of Minimal Residual Disease; Malignancy. 1139 36


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