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)

In acute myeloid leukaemia (AML), involvement of early progenitor cells may predict poor response to induction chemotherapy. We evaluated the involvement of early progenitor cells in two AML subtypes with a favourable prognosis [t(8;21) and t(15;17)], and a subtype with poor prognosis (monosomy 7). CD34+CD33- cells were isolated by fluorescence-activated cell sorting, grown in liquid medium followed by culture in semi-solid medium, and the colonies that were formed were analysed for the identifiable genetic markers. Two of 136 colonies from six t(8;21) AML patients expressed the AML1-ETO transcript, and all six patients achieved remission after induction. None of 192 colonies from five t(15;17) AML patients expressed the RARalpha-PML transcript and all achieved remission. In contrast, in three of 10 cases of monosomy 7 AML, colonies were positive for monosomy 7, and all three patients failed to enter remission. However, five of six evaluable patients with colonies negative for monosomy 7 entered remission. These data support the hypothesis that leukaemic involvement of early progenitor cells affects the response to induction chemotherapy.
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PMID:Progenitor cell involvement is predictive of response to induction chemotherapy in paediatric acute myeloid leukaemia. 1461 1

The eight-twenty-one (ETO) homologues, represented by ETO, myeloid transforming gene-related protein 1 (MTGR1) and myeloid transforming gene chromosome 16 (MTG16), are nuclear repressor proteins. ETO is part of the fusion protein acute myeloid leukaemia (AML)1-ETO, resulting from the translocation (8;21). Similarly, MTG16 is disrupted to become part of AML1/MTG16 in t(16;21). The aberrant expression of these chimeras could affect interplay between ETO homologues and contribute to the leukaemogenic process. We investigated possible interactions between the ETO homologues. Ectopic co-expression in COS-cells resulted in heterodimerisation of the various ETO homologues suggesting that they may co-operate. Similarly, the chimeric oncoprotein AML1-ETO interacted with both MTGR1 and MTG16. However, results from cell lines endogenously expressing more than one ETO homologue did not demonstrate co-precipitation. Results from IP-Western and size determination by gel filtration of deletion mutants expressed in COS-cells, indicated an important role of the HHR domain for oligomerisation. A role was also suggested for the Nervy domain in the homologue interactions. Our results suggest that ETO homologues can interact with each other as well as with AML1-ETO, although it is unclear as to what extent these interactions occur in vivo.
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PMID:Interactions between the leukaemia-associated ETO homologues of nuclear repressor proteins. 1470 94

The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.
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PMID:Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. 1502 77

The Runt domain transcription factor, PEBP2/CBF, is a heterodimer composed of 2 subunits. The DNA-binding alpha subunit, or RUNX protein, interacts with a partner PEBP2beta/CBFbeta through the evolutionarily conserved Runt domain. Each of the genes encoding RUNX1 and PEBP2beta/CBFbeta is frequently involved in acute myeloid leukemia. The chimeric protein, CBFbeta(PEBP2beta)/SMMHC, is generated as a result of inversion of chromosome 16 in such a way to retain the heterodimerization domain of PEBP2beta at the amino-terminal side fused to the C-terminal coiled-coil region of smooth muscle myosin heavy chain (SMMHC). Here we show that, in the chimeric protein, the second heterodimerization domain is created by the fusion junction, enabling the chimeric protein to interact with RUNX1 at far greater affinity than PEBP2beta and inactivate the RUNX1/AML1 function. To explain why and how heterozygous CBFB/MYH11 can inactivate homozygous RUNX1 near to completion, we propose a new model for this chimeric protein that consists of a Y-shaped dimer with unpaired N-terminal halves followed by a coiled-coil for the C-terminal region.
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PMID:Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera. 1507 Jul 3

The AML1-ETO fusion has been associated with up to 40% of acute myeloid leukaemia French-American-British classified M2 cases. This chimaeric protein interferes with normal AML1 function and disrupts critical transcriptional regulation of haematopoiesis. Current evidence suggests that AML1-ETO alone is insufficient to induce leukaemia, but rather is a co-operating event in leukaemogenesis. We developed a pluripotent murine haematopoietic stem cell line expressing the AML1-ETO fusion protein that displays in vitro and in vivo properties consistent with a preleukaemic state, including inhibition of terminal granulocytic differentiation in vitro and the development of non-lymphoid leukaemias in vivo. This cell line represents a potential platform for the introduction and in vitro rapid screening of candidate genes thought to co-operate with AML1-ETO in developing frank leukaemia.
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PMID:Establishment of a pluripotent preleukaemic stem cell line by expression of the AML1-ETO fusion protein in Notch1-immortalized HSCN1cl10 cells. 1508 16

Retroviral insertional mutagenesis in BXH2 mice commonly induces myeloid leukemias. One of the most frequently involved genes in experimental studies is Meis 1. In contrast to other genes in murine models, Meis 1 has not been affected by recurrent chromosomal translocations or point mutations in human leukemias. We found a constant downregulation of the Meis 1 gene mRNA in AML1-ETO acute myeloid leukemias and in those cases harboring in frame mutations in the bZIP domain of CEBPalpha. The absence of the Meis 1 mRNA was not caused by inactivating point mutations in the coding sequence. Promoter hypermethylation was present in more than half of the cases (9/14), including samples obtained from the widely employed Kasumi-1 cell line. Double treatment with 5-Aza-2'-deoxycytidine and trichostatin A of the Kasumi-1 cell line partially reverses Meis 1 inhibition. HoxA9 levels were also low. In a cell line model (U937 Tet AML1-ETO), AML1-ETO expression was not associated with Meis 1 suppression at 72 h. Nevertheless, Meis 1 repression is dependent on the AML1-ETO transcript levels in treated leukemic patients. Chimeric products that arise from chromosomal translocations may be associated with locus-specific epigenetic inactivation. It remains to be investigated when this methylation process is acquired and which are the basic mechanisms underlying these molecular events in AML1-ETO and CEBPalpha-mutated AML.
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PMID:MEIS 1 expression is downregulated through promoter hypermethylation in AML1-ETO acute myeloid leukemias. 1510 90

The (8;21) translocation between the AML1 and ETO genes is seen in approximately 12-15% of all acute myeloid leukemia (AML) and is a frequently observed nonrandom genetic alteration associated with AML. The ETO moiety was shown to interact with the nuclear receptor co-repressor (N-CoR) complex, which includes mSin3A and the histone deacetylase, HDAC1. Repression of AML1-responsive hematopoietic genes by AML1-ETO and the N-CoR complex may play a mechanistic role in t(8;21) leukemogenesis. In order to characterize the interaction between ETO and N-CoR, mutants of either protein were constructed and tested for binding in both yeast two-hybrid and immunoprecipitation assays. We found that two domains of human N-CoR, amino acid residues 988-1126 and 1551-1803, were necessary for interaction with ETO. Previously, we and other investigators had reported that two unusual zinc finger motifs at the C-terminus of ETO mediated binding to N-CoR. Here, using mammalian two-hybrid assays, we found that transcription repression by ETO was substantially decreased when either zinc finger motif of ETO is deleted or mutated. In addition, we identified a second transcription repression domain located between residues 275 and 487. Characterization of the ETO interaction domains within human N-CoR and of the transcription domains of ETO is a first step in designing targeted molecular therapy for t(8;21) AML.
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PMID:Domains involved in ETO and human N-CoR interaction and ETO transcription repression. 1510 42

Following induction chemotherapy for acute myeloid leukaemia (AML), sensitive determination of minimal residual disease (MRD) in patients achieving complete remission (CR) should enable the detection of early relapse and allow intervention at a more favourable stage than at overt relapse. We have determined the expression levels of the Wilms' tumour gene (WT1) by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood and bone marrow in 133 newly diagnosed AML patients and compared them with those in healthy volunteers. At diagnosis, the WT1 level exceeded normal expression in 118 of 133 (89%) patients, and was high enough to allow for detection of a WT1 decrease of least 1000-fold in 98 of 133 (74%) patients following induction therapy. Concomitant monitoring of fusion transcripts (PML-RARalpha, AML1-ETO, MLL-MLL, CBFbeta-MYH11, or DEK-CAN) in 38 patients identified different relationships between WT1 and fusion transcript levels, the AML1-ETO group showing remarkably low levels of WT1 compared with fusion transcript. In 32 patients analysed longitudinally there was close concordance between relapse and increased WT1 levels. Parallel longitudinal monitoring of WT1 and fusion transcript showed close correlation in 18 of 18 patients. We conclude that WT1 expression by RQ-PCR may be employed as a tool to detect MRD in the majority of fusion transcript-negative AML patients.
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PMID:WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients - results from a single-centre study. 1514 74

The t(8;21) translocation is one of the most frequent translocations in acute myeloid leukaemia (AML), giving rise to the AML1-ETO fusion protein (or RUNX1-CBF2T1). This abnormality is associated with myelocytic leukaemia with dysplastic granulopoiesis. Here, we demonstrate that when expressed in a normal human (CD34(+)) progenitor population, AML1-ETO selectively inhibits granulocyte colony formation but not monocyte colony formation. In bulk liquid culture, we found that though AML1-ETO transiently inhibited the proliferation of CD34(+) cells, it promoted long-term growth of myeloid cells for more than 80 days, suggesting that differentiation was inhibited. In support of this, cultures expressing AML1-ETO demonstrated enhanced retention of colony-forming capacity. Phenotypic examination of AML1-ETO cultures revealed a defect in granulocytic differentiation in terms of retention of CD34(+) cells within the culture and delayed CD11b upregulation. Morphologically, granulocyte terminal differentiation in AML1-ETO-expressing cells was inhibited by 83+/-5%, giving rise to a build-up of early to intermediate granulocytes that exhibited a number of morphological features associated with t(8;21) leukaemias. In contrast, AML1-ETO had little or no effect on monocytic differentiation. Taken together, these results suggest that expression of AML1-ETO selectively inhibits the differentiation of granulocytic cells and promoted extensive self-renewal, supporting a causal role for t(8;21) translocations in leukaemogenesis.
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PMID:Expression of AML1-ETO in human myelomonocytic cells selectively inhibits granulocytic differentiation and promotes their self-renewal. 1515 69

Insights into the pathogenesis of human leukemia have relied heavily on studies of the identified chromosomal translocations found in this group of malignant diseases. Acquired, balanced translocations in acute myelogenous leukemia (AML) generally involve transcriptional regulatory genes, whereas in the myeloproliferative disorders tyrosine kinases are frequently involved. These rearrangements alter the function of at least one and often both of the involved genes. In this review, we focus on the AML1-ETO (a.k.a. RUNX1-ETO) fusion protein, which is found in t(8;21)+ AML. Expression of AML1-ETO in human hematopoietic stem cells (HSCs) preferentially enhances their maintenance, as opposed to their differentiation. The direct effects of AML1-ETO on human and murine HSCs, and the potentially cooperating events that may contribute to its leukemogenic properties, are discussed.
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PMID:Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells. 1515 80


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