Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AML1-MTG8 fusion protein, which is produced from the rearranged gene formed between AML1 and MTG8 in myeloid leukemia with t(8;21) chromosomal translocation, plays an important role in the pathogenesis of leukemia. We previously showed that ectopically expressed AML1-MTG8 fusion protein is associated with an MTG8-like protein in the mouse myeloid precursor cell line L-G, and this association seemed to be required for AML1-MTG8 to stimulate proliferation. As a candidate cDNA for this MTG8-like protein, a 6.4 kb MTGR1 cDNA encoding human MTGR1b protein of 604 amino acids was isolated. Since this cDNA was shorter than the main mRNA (about 7.5 kb), the 5'-end of the MTGR1 cDNA was extended using Marathon Ready cDNA. When the newly obtained 5'-sequence was combined with the previous cDNA, the resultant MTGR1 cDNA (6995 bp), including exon 3 that the previous cDNA lacked, could encode MTGR1a protein of 575 amino acids. Transcripts of the MTGR1 gene were expressed ubiquitously in the human tissues and cell lines examined. PCR analyses of the cDNAs from human tissues showed the presence of various splicing variants with regard to the 5'-region including exons 1, 2 and 3. The MTGR1 gene consists of 14 exons and spans about 68 kb. The genomic structure of MTGR1 is highly similar to those of other MTG 8-family genes, MTG8 and MTG16. MTG16 was recently cloned from the translocation breakpoint of myeloid malignancies with t(16;21) chromosomal translocation.
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PMID:Structure and expression pattern of a human MTG8/ETO family gene, MTGR1. 1067 41

We evaluated the usefulness of a recently developed real-time reverse transcriptase polymerase chain reaction (RT-PCR) system to detect minimal residual diseases (MRD) in patients with acute myelogenous leukaemia (AML) with chromosomal translocation t(8:21). The method was simple, rapid and reproducible for the quantity of chimeric AML1-ETO (MTG8) transcripts. The ratio of the absolute copy number of a target gene (AML1-ETO) to a control gene (glyceraldehyde-3-phosphate dehydrogenase, GAPDH) was calculated by using a fluorescence curve prepared from amplicons of serially diluted standard RNA. The relative points of MRD in bone marrow (BM) of 8 patients in the acute phase of the disease was from 0.85 to 3.0, whereas those of MRD in complete remission (CR) decreased to below 6.4 x 10(-3). This method was also applied to evaluate chimeric transcripts in peripheral blood (PB) samples. The values in patients with t(8;21) AML were from 0.97 to 2.0 in the acute phase, whereas those in CR showed less than 2.2 x 10(-4). There was 10(-5)-fold difference in AML1-ETO mRNA expression between PB samples in the acute phase and those in CR. The results suggest that we may easily monitor MRD in patients with t(8;21) AML through quantitative analysis of AML1-ETO transcripts in blood samples.
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PMID:A quantitative reverse transcriptase polymerase chain reaction method for the detection of leukaemic cells with t(8;21) in peripheral blood. 1077 97

Leukemia-specific AML1/ETO transcripts are detectable in most patients with t(8;21) acute myelogenous leukemia (AML) in long-term remission. To understand the inconsistency between the clinical cure and the presence of "residual disease" at a molecular level, we separated and identified the cells expressing AML1/ETO by phenotype and function. Here we demonstrate that AML1/ETO transcripts are present in a fraction of stem cells, monocytes, and B cells in remission marrow, and in a fraction of B cells in leukemic marrow, but not in T cells. AML1/ETO transcripts also were demonstrated in a fraction of colony-forming cells of erythroid, granulocyte-macrophage, and/or megakaryocyte lineages in both leukemic and remission marrow. These data strongly suggest that the acquisition of the t(8;21) occurs at the level of stem cells capable of differentiating into B cells as well as all myeloid lineages, and that a fraction of the AML1/ETO-expressing stem cells undergo additional oncogenic event(s) that ultimately leads to transformation into AML.
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PMID:AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation. 1086 Oct 16

A patient with acute myeloid leukemia (AML)-M2 with t(8;21)(q22;q22) achieved complete remission with remission-induction chemotherapy followed by consolidation and intensification chemotherapies. T(8;21)(q22;q22) disappeared, but chimeric AML1/MTG8 was continuously detected in bone marrow cells. Following the development of therapy-related leukemia after 1 year, evolution of therapy-related AML-M4 with t(11;17)(q23;q25) and the rearrangement of the MLL gene were observed, while AML/MTG8 disappeared. After reinduction and following intermittent chemotherapies, a subsequent alternative transformation to AML-M2 occurred after detection of t(3;21)(q21;q22), with a break in the AML1 gene shown by interphase fluorescence in situ hybridization analysis. This leukemia transformed to AML-M4 after t(9;22)(q34;q11), with a minor BCR/ABL rearrangement, and then finally to AML-M2. This therapy-related leukemia was resistant to chemotherapy. These findings indicate that alterations in cytogenetic and molecular events caused by chemotherapeutic agents contribute to the sequential evolution of new leukemic clones with different morphology.
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PMID:Morphological and cytogenetic changes in therapy-related leukemia developed in a t(8;21)-acute myeloid leukemia (M2) patient: sequential cytogenetic and molecular analyses. 1090 55

Promyelocytic leukemia (PML) nuclear bodies are important components of nuclear architecture that are functionally linked to aberrant gene expression and disease. To understand the mechanisms that modify subnuclear distribution and regulatory activities of PML domains in leukemia, we performed immunofluorescence microscopy with a panel of normal diploid cells and established cell lines. We analyzed the representation and intranuclear distribution of PML domains. We find that multiple biological parameters contribute to heterogeneity in the subnuclear organization of PML domains in a broad spectrum of cell types. The subnuclear organization of PML domains was also evaluated following transient transfection with a series of vectors expressing normal hematopoietic and leukemia-related transcription factors. Our results show that expression of a chimeric transcription factor encoded by the tumor related chromosomal translocation (8;21) involving the AML1 and ETO loci is sufficient to cause reorganization of PML domains. This finding increases our understanding of the mechanisms by which the AML1/ETO protein may contribute to modified gene expression linked to the onset and progression of t(8;21) related acute myelogenous leukemia.
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PMID:Leukemia-associated AML1/ETO (8;21) chromosomal translocation protein increases the cellular representation of PML bodies. 1090 59

Dentato-rubral and pallido-luysian atrophy (DRPLA) is one of the family of neurodegenerative diseases caused by expansion of a polyglutamine tract. The drpla gene product, atrophin-1, is widely expressed, has no known function or activity, and is found in both the nuclear and cytoplasmic compartments of neurons. Truncated fragments of atrophin-1 accumulate in neuronal nuclei in a transgenic mouse model of DRPLA, and may underlie the disease phenotype. Using the yeast two-hybrid system, we identified ETO/MTG8, a component of nuclear receptor corepressor complexes, as an atrophin-1-interacting protein. When cotransfected into Neuro-2a cells, atrophin-1 and ETO/MTG8 colocalize in discrete nuclear structures that contain endogenous mSin3A and histone deacetylases. These structures are sodium dodecyl sulfate-soluble and associated with the nuclear matrix. Cotransfection of ETO/MTG8 with atrophin-1 recruits atrophin-1 to the nuclear matrix, while atrophin-1 and ETO/MTG8 cofractionate in nuclear matrix preparations from brains of DRPLA transgenic mice. Furthermore, in a cell transfection-based assay, atrophin-1 represses transcription. Together, these results suggest that atrophin-1 associates with nuclear receptor corepressor complexes and is involved in transcriptional regulation. Emerging links between disease-associated polyglutamine proteins, nuclear receptors, translocation-leukemia proteins, and the nuclear matrix may have important repercussions for the pathobiology of this family of neurodegenerative disorders.
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PMID:Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription. 1097 86

We report a case of acute myelocytic leukemia (AML) showing a chromosomal abnormality, ins(21;8), with AML1/MTG8 chimeric mRNA. The patient, a 73-year-old woman, was admitted to our hospital because of AML relapse. Bone marrow aspiration showed 44% blasts and ins(21;8)(q12;q13q22) by cytogenetic study. Moreover, the size of chimeric AML1/MTG8 mRNA detected by RT-PCR in this case was shorter than that of previously reported. The patient was diagnosed as having relapse of AML (M2), but achieved complete remission with DCP therapy. Four months later, extramedullary relapse occurred, and this was followed five months later by bone marrow relapse. However, the patient again achieved complete remission. Most cases of AML1/MTG8 fusion gene are caused by t(8;21), and only very rarely by ins(21;8). In this case, the AML1/MTG8 fusion gene is thought to have been involved in the onset of leukemia.
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PMID:[Acute myelocytic leukemia with ins(21;8)(q22;q13q22) presenting with AML1/MTG8 chimeric mRNA]. 1107 Sep 37

The AML-1/ETO fusion protein, created by the (8;21) translocation in M2-type acute myelogenous leukemia (AML), is a dominant repressive form of AML-1. This effect is due to the ability of the ETO portion of the protein to recruit co-repressors to promoters of AML-1 target genes. The t(11;17)(q21;q23)-associated acute promyelocytic leukemia creates the promyelocytic leukemia zinc finger PLZFt/RAR alpha fusion protein and, in a similar manner, inhibits RAR alpha target gene expression and myeloid differentiation. PLZF is expressed in hematopoietic progenitors and functions as a growth suppressor by repressing cyclin A2 and other targets. ETO is a corepressor for PLZF and potentiates transcriptional repression by linking PLZF to a histone deacetylase-containing complex. In transiently transfected cells and in a cell line derived from a patient with t(8;21) leukemia, PLZF and AML-1/ETO formed a tight complex. In transient assays, AML-1/ETO blocked transcriptional repression by PLZF, even at substoichiometric levels relative to PLZF. This effect was dependent on the presence of the ETO zinc finger domain, which recruits corepressors, and could not be rescued by overexpression of co-repressors that normally enhance PLZF repression. AML-1/ETO also excluded PLZF from the nuclear matrix and reduced its ability to bind to its cognate DNA-binding site. Finally, ETO interacted with PLZF/RAR alpha and enhanced its ability to repress through the RARE. These data show a link in the transcriptional pathways of M2 and M3 leukemia. (Blood. 2000;96:3939-3947)
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PMID:AML-1/ETO fusion protein is a dominant negative inhibitor of transcriptional repression by the promyelocytic leukemia zinc finger protein. 1109 81

Several reports have demonstrated the persistent detection of AML1-MTG8 fusion products, representing minimal residual disease (MRD), in patients with t(8;21) acute myelogenous leukaemia (AML) who are in long-term remission. It is probable that immune-mediated mechanisms that are able to suppress the expansion of MRD may result in the continuance of remission. It was previously shown that some t(8;21) AML patients had high anti-MTG8 antibody titres. MTG8 expression in normal adult tissues is limited to the brain or heart in which human leucocyte antigen (HLA) class I cell-surface antigens are either not or are only faintly detectable. We hypothesized that the overexpression of the MTG8 gene in t(8;21) AML cells could act as a possible tumour antigen, which might be able to induce the immune-mediated suppression of the expansion of MRD. We were able to induce HLA-A0201-restricted cytotoxic T-lymphocyte (CTL) lines against an MTG8 peptide (MTG8b amino acids 182-191) using monocyte-derived dendritic cells from a healthy donor. T-cell receptor (TCR)Valpha17, TCRVbeta14 and 15, and TCRJbeta2.1 and 2.3 are predominantly used in these CTL lines. Our data, which suggest that the MTG8 protein could be one of the tumour antigens recognized by CTLs, may be helpful in further investigations of TCR analysis in t(8;21) AML patients with HLA-A0201 who are in long-term remission.
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PMID:Induction of MTG8-specific cytotoxic T-cell lines: MTG8 is probably a tumour antigen that is recognized by cytotoxic T cells in AML1-MTG8-fused gene-positive acute myelogenous leukaemia. 1112 5

The molecular analysis of recurring chromosome rearrangements, especially of translocations and inversions, has provided us with valuable insight into the pathogenesis of hematological malignancies. Many translocations result in the fusion of genes located at the translocation breakpoints. In recent years we have witnessed a rapid rise in the number of chromosome translocations in leukemias being characterized at the molecular level. However, the number of genes being newly identified as translocation fusion genes has not risen at the same pace. This is due to the fact that several genes are involved in more than one translocation forming fusion genes with a number of other partner genes. Not only does one find star-shaped topologies, with one gene forming fusions with several others (e.g. ETV6/PDGFRB, ETV6/JAK2, ETV6/ABL etc.), but also networks connecting several genes with more than one fusion partner (e.g. ETV6/RUNX1 (AML1), RUNX1/CBFA2T1 (ETO), ETV6/EVI1, RUNX1/EVI1, ETV6/ABL, BCR/ABL). The emergence of such networks with the "recycling" of genes in new fusion combinations suggests that there is a rather limited number of genes which can be altered to cause leukemia.
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PMID:Fusion genes in leukemia: an emerging network. 1117 30


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