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)

The (8;21) chromosomal translocation occurs in 20% of adult patients with AML M2. This translocation interrupts two genes, AML1 on chromosome 21q and MTG8 (ETO) on 8q to form a chimeric gene AML1/MTG8 on the der(8) chromosome. Recent reports have shown the presence of diverse forms of transcript for this chimeric gene. Three alternative out-of-frame transcripts have been previously demonstrated (types II, III, IV) all of which have a stop codon 3' of the runt box encoding a truncated runt polypeptide. We have characterized a novel transcript (V) which is in-frame and has a stop codon 3' to the runt box. We have examined transcript diversity in 10 AML patients with t(8;21) in remission of their disease following chemotherapy or bone marrow transplantation. Specific transcripts detected at presentation in six patients were similarly expressed during remission and at relapse in two patients; thus expression of transcript diversity was unaffected by the disease phase. Alternative transcripts were unhelpful as a marker of remission quality or predictor of relapse. The significance of these diverse transcripts in leukemogenesis remains unknown.
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PMID:Expression of diverse AML1/MTG8 transcripts is a consistent feature in acute myeloid leukemia with t(8;21) irrespective of disease phase. 868 93

AML-1B is targeted directly and indirectly in multiple chromosomal translocations in myeloid and B-cells. The AML-1/ETO and TEL/AML-1 fusion proteins, created by the t(8;21) and t(12;21) respectively, disrupt AML-1B-dependent transcription. Recently, two human members of the runt homology domain family of transcription factors have been identified, AML-2 and AML-3, which also regulate transcription through enhancer core motifs. If multiple factors regulate transcription through the same site, a dominant interfering protein may be required to promote leukemogenesis, rather than the inactivation of both AML1 alleles. To determine which AML family proteins are active in hematopoietic cells, we developed antisera specific to each family member for use in gel mobility shift assays. We have found that AML-1B is the major DNA binding activity in T-cell lines, while both AML-1B and AML-2 are expressed in myeloid and B-cell lines. AML-1B represents most of the active protein in the mouse thymus, whereas AML-1 and AML-2 are equally expressed in the mouse spleen. AML-3 is expressed at very low levels in a single myeloid cell line, 32D.3, and is the only core binding activity present in Buffalo rat liver cells. We demonstrate that AML-2-dependent transactivation mediated by enhancer core motifs is inhibited by the AML-1/ETO and TEL/AML-1 fusion proteins. This indicates that the t(8;21) and t(12;21) fusion proteins inhibit transcriptional activation by the AML-1 transcription factor family, and in so doing contributes to leukemogenesis.
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PMID:AML-2 is a potential target for transcriptional regulation by the t(8;21) and t(12;21) fusion proteins in acute leukemia. 871 Mar 69

We present a case of a 59-year-old Japanese man with therapy-related acute myeloblastic leukemia (AML) after the chemotherapy for non-Hodgkin's lymphoma (NHL). Accumulated doses of cyclophosphamide, procarbazine, doxorubicin, mitoxantrone, and etoposide were 18,300 mg, 3000 mg, 580 mg, 100 mg, and 4150 mg, respectively, which had been administered for the treatment of NHL. Myeloblasts in the peripheral blood increased 43 months after the onset of NHL. He was diagnosed as having AML (M2; FAB classification). The karyotype of the bone marrow cells in the present case contained the following abnormalities: t(2;21)(q21;q22), t(8;21)(q22;q22), and add(13)(q34). In the present case, 645 base pairs of chimeric mRNA were detected by reverse transcription-polymerase chain reaction, indicating the presence of AML1/MTG8 rearrangement. Translocation (2;21)(q21;q22) has not been described previously to our knowledge. It is interesting that the breakpoint of 21q22 existed both in t(2;21) and t(8;21). The disrupted AML1 gene resulting from two 21q22 rearrangements may be involved in the pathogenesis of AML in the present case. The clinical importance of therapy-related AML having the 21q22 rearrangement remains to be examined.
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PMID:Therapy-related leukemia with a novel 21q22 rearrangement. 878 Jul 46

GM-CSF gene activation in T cells is known to involve the transcription factors nuclear factor-kappa B, AP-1, NFAT, and Sp1. Here we demonstrate that the human GM-CSF promoter and enhancer also encompass binding sites for core-binding factor (CBF). Significantly, the CBF sites are in each case contained within the minimum essential core regions required for inducible activation of transcription. Furthermore, these core regions of the enhancer and promoter each encompass closely linked binding sites for CBF, AP-1, and NFATp. The GM-CSF promoter CBF site TGTGGTCA is located 51 bp upstream of the transcription start site and also overlaps a YY-1 binding site. A 2-bp mutation within the CBF site resulted in a 2-3-fold decrease in the activities of both a 69-bp proximal promoter fragment and a 627-bp full-length promoter fragment. Stepwise deletions into the proximal promoter also revealed that the CBF site, but not the YY-1 site, was required for efficient induction of transcriptional activation. The AML1 and CBF beta genes that encode CBF each have the ability to influence cell growth and differentiation and have been implicated as proto-oncogenes in acute myeloid leukemia. This study adds GM-CSF to a growing list of cytokines and receptors that are regulated by CBF and which control the growth, differentiation, and activation of hemopoietic cells. The GM-CSF locus may represent one of several target genes that are dysregulated in acute myeloid leukemia.
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PMID:Regulation of GM-CSF gene transcription by core-binding factor. 880 9

The AML1/ETO fusion transcript is expressed in virtually all patients with t(8;21) (q22;q22) acute myeloid leukemia (AML). The fusion transcript can be detected by reverse transcription-polymerase chain reaction (RT-PCR) in most of these patients in long-term complete remission (CR) following conventional chemotherapy or autologous bone marrow transplantation (BMT). However, AML1/ETO expression has not been analyzed in a series of patients following allogeneic BMT. We examined CR bone marrow (BM) samples and, in some cases, blood samples from 10 patients with t(8;21) leukemia who underwent allogeneic BMT in either first or second remission or first or second relapse. A variety of myeloablative regimens were used. Eight patients received non-T-cell depleted BM from matched sibling donors, one patient received a T-cell depleted haploidentical BM, and one patient received a non-T-cell depleted BM from a matched unrelated donor (MUD). Five patients developed acute and/ or chronic graft versus host disease (GVHD). The furthest time points analyzed for the AML1/ETO transcript in the 10 patients in CR following allogeneic BMT ranged from 7.5 to 83.0 months. Sufficient RNA was extracted from the most recent BM or BM and blood samples from nine patients to assay for presence or absence of the AML1/ETO fusion transcript by RT-PCR. The fusion transcript was detected by RT-PCR in all nine of these patient samples; eight were positive in BM and one was negative in BM, but positive in blood. The fusion transcript could not be detected in a BM sample from the tenth patient obtained 7.5 months after BMT, but the amount of RNA available was suboptimal. Hematopoietic chimerism could be demonstrated in sorted CD34+ BM cells from two of four patient CR BM samples with RT-PCR evidence of the fusion transcript. Additionally, in one of the two cases with chimerism, we demonstrated an abnormal clonal population of recipient cells in the CR BM sample by fluorescence in situ hybridization. One patient died of complications from GVHD, while the other nine patients remain alive without evidence of relapse, with a median follow-up time of 27 (range, 7.5 to 87) months post-BMT. These data suggest that allogeneic BMT, like conventional chemotherapy and autologous BMT, is not sufficient to eradicate cells expressing AML1/ETO, and that a positive RT-PCR for the fusion transcript post allogeneic BMT is compatible with continued CR.
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PMID:Persistence of the AML1/ETO fusion transcript in patients treated with allogeneic bone marrow transplantation for t(8;21) leukemia. 937 7

The chromosomal translocation (8;21)(q22;q22) in the AML M2 subtype according to the FAB classification, results in the production of a novel fusion gene AML1/ETO. The chimaeric AML1/ETO transcript is useful for the detection of minimal residual disease (MRD). Recently, several studies on the detection of AML1/ETO transcripts in t(8;21) AML have been reported. However, the clinical significance of a small number of AML1/ETO transcripts by a reverse transcription-polymerase chain reaction (RT-PCR) remains to be elucidated. We have developed a novel quantitative RT-competitive PCR assay and evaluated the clinical usefulness of this method by the monitoring of MRD in eight patients with t(8;21) AML. In four patients in first continuous complete remission (CR) the value of MRD was always < 0.1 fg of the competitor dose throughout their courses, whereas in four relapsed patients there was an increase in the value of MRD to > 0.1 fg of the competitor dose before cytogenetic relapse. We conclude that the detection of the presence of cells with AML1/ETO fusion transcripts by our RT-competitive PCR assay may be useful to monitor disease progression and to predict subsequent relapse.
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PMID:Serial quantification of minimal residual disease of t(8;21) acute myelogenous leukaemia with RT-competitive PCR assay. 885 43

The alterations of transcription factor genes by chromosomal translocations play an important role in leukemogenesis and lymphomagenesis. The alterations are classified into two groups. One is the chimeric gene formation, and the other is the aberrant expression without structural changes. The former type is associated with the chromosomal translocations found in acute myeloid leukemia, such as the AML1/MTG8 in t(8;21) and PML/RAR alpha in t(15;17). The latter is the main mechanism in the gene activations observed in acute lymphoblastic leukemia and lymphoma. Many transcription factor genes are activated by the recombination with the immunoglobulin genes in B cell malignancies or T cell receptor genes in T cell malignancies. We isolated the AML1/EVI-1 fusion gene generated by the t(3;21) translocation, which is usually found in blastic crisis of chronic myelocytic leukemia. The chimeric transcription factor encoded by the fusion gene has dual functions, namely differentiation block and stimulation of proliferation. These findings provide new insight into the molecular mechanism in leukemogenesis by the chimeric transcription factors.
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PMID:Chromosomal abnormalities and oncogenes. 886 20

AML1 is involved in the (8;21) translocation, associated with acute myelogenous leukemia (AML)-type M2, which results in the production of the AML1-ETO fusion protein: the amino-terminal 177 amino acids of AML1 and the carboxyl-terminal 575 amino acids of ETO. The mechanism by which AML1-ETO accomplishes leukemic transformation is unknown; however, AML1-ETO interferes with AML1 transactivation of such AML1 targets as the T-cell receptor beta enhancer and the granulocyte-macrophage colony-stimulating factor promoter. Herein, we explored the effect of AML1-ETO on regulation of a myeloid-specific AML1 target, the macrophage colony-stimulating factor (M-CSF) receptor promoter. We found that AML1-ETO and AML1 work synergistically to transactivate the M-CSF receptor promoter, thus exhibiting a different activity than previously described. Truncation mutants within the ETO portion of AML1-ETO revealed the region of ETO necessary for the cooperativity between AML1 and AML1-ETO lies between amino acids 347 and 540. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient with AML-M2 t(8;21) and the promonocytic cell line U937. Kasumi-1 cells exhibited a significantly higher level of M-CSF receptor expression than U937 cells. Bone marrow from patients with AML-M2 t(8;21) also exhibited a higher level of expression of M-CSF receptor compared with normal controls. The upregulation of M-CSF receptor expression by AML1-ETO may contribute to the development of a leukemic state in these patients.
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PMID:Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis. 887 34

Spontaneous remissions of acute myeloid leukemia (AML) have been documented in association with infection as well as blood transfusions. Activation of the immune system including an increased number of NK cells and cytokine release have been implicated in the mechanism of this phenomenon. We have observed spontaneous remissions in two patients with AML (one with a t(8;21)-positive M2, one with M5b), both occurring after infection and blood transfusions. The bone marrow showed a reduction of blast cells from 65% to 2% or 40% to 1%, respectively. Remission was accompanied by a marked polyclonal hypergammaglobulinemia in both cases (IgG values of 6420 and 2160 mg/dl, IgA of 802 and 811 mg/dl, respectively). A concomitant increase in bone marrow plasma cells was observed in both patients. Reduction of AML1/ETO PCR positivity from one-step to two-step PCR (approximately 100-fold) was documented in the patient with a t(8;21), while a regression of lymph node and skin leukemic infiltrations occurred in the patient with M5b. One patient relapsed after 4 months, at a time when his serum immunoglobulin levels had markedly decreased. The other patient is in continuous remission after 14 months. These cases suggest a potential role for a humoral immune response in the mechanism of spontaneous remission.
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PMID:Spontaneous remission of acute myeloid leukemia after infection and blood transfusion associated with hypergammaglobulinaemia. 889 Jul 8

We have developed a quantitative reverse transcriptase-polymerase chain reaction method for the quantitation of AML1-MTG8 transcripts in patients with AML-M2 and t(8;21) in different phases of the disease. Using this method, we have tested sequential samples from 13 patients to monitor minimal residual disease and were able to show a significant increase in AML1-MTG8 transcripts level in two patients 2 and 4 months before clinical relapse. In five patients tested at presentation and then sequentially at remission, we detected a marked decrease in the level of AML1-MTG8 transcripts as the treatment progressed. Patients in long-term remission of their disease had a level of up to 1 x 10(3) AML1-MTG8 molecules/microgram RNA. Two patients tested 2 and 4 months before hematologic relapse showed a level of 0.71 x 10(5) molecules/microgram RNA and this level increased further during relapse to 0.71 x 10(7) and 2.27 x 10(5) molecules/microgram RNA, respectively. Our results show that quantitation of AML1-MTG8 transcripts by competitive polymerase chain reaction is valuable in predicting early relapse in AML with t(8;21). Identification of at-risk patients may allow treatment to be modified to include additional or alternative therapy such as bone marrow transplantation.
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PMID:Monitoring of minimal residual disease by quantitative reverse transcriptase-polymerase chain reaction for AML1-MTG8 transcripts in AML-M2 with t(8; 21). 891 34


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