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)

The Moloney murine leukemia virus (Mo-MLV) enhancer contains binding sites (LVb and LVc) for the ets gene family of proteins and a core site that binds the polyomavirus enhancer-binding protein 2/core-binding factor (cbf) family of proteins. The LVb and core sites in the Mo-MLV enhancer contribute to its constitutive activity in T cells. All three binding sites (LVb, LVc, and core) are required for phorbol ester inducibility of the Mo-MLV enhancer. Adjacent binding sites for the ets and cbf proteins likewise constitute a phorbol ester response element within the human T-cell receptor beta-chain (TCR beta) enhancer and contribute to constitutive transcriptional activity of the TCR beta enhancer in T cells. Here we show that the CBF alpha subunit encoded by the mouse Cbfa2 gene (the murine homolog of human AML1) and three ets proteins, Ets-1, Ets-2, and GA-binding protein (GABP), transactivate both the Mo-MLV and mouse TCR beta enhancer in transient-expression assays. Moreover, we show that transactivation by Cbf alpha 2 requires both intact ets and cbf binding sites. Transactivation by Ets-1, Ets-2, and GABP likewise requires intact binding sites for ets proteins and CBF. Supportive biochemical analyses demonstrate that both proteins can bind simultaneously to a composite enhancer element. These findings suggest that ets and cbf proteins cooperate in vivo to regulate transcription from the Mo-MLV and TCR beta enhancers.
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PMID:Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins. 760 63

The t(8;21) is a frequent chromosome abnormality in acute myeloid leukemia (AML), particularly associated with M2 of the French-American-British (FAB) classification, but also found in a few patients with myelodysplastic syndrome (MDS). The two genes involved in the t(8;21) have been recently isolated and the cDNA of the AML1/ETO fusion gene identified. We have investigated a series of AML and MDS patients by a reverse transcriptase-polymerase chain reaction (RT-PCR) and analyzed the clinical and laboratory features of leukemia with t(8;21). The t(8;21) was only found in a subset of M2, which had the clinical and hematological features distinct from those M2 without t(8;21). M2 with t(8;21) was associated with a significantly higher myeloid differentiation and with a good response to chemotherapy. Moreover, among the patients with refractory anemia with excess of blasts in transformation (RAEB-T) the t(8;21) was also significantly associated with a higher myeloid differentiation and a good response to chemotherapy. M2 patients with t(8;21) could be distinguished on a number of hematological parameters, eg white blood cell count and percentage of bone marrow myeloblasts and promyelocytes, from RAEB-T carrying the t(8;21). Based on these findings we suggest that leukemia patients carrying t(8;21) can be grouped into two types; overt acute myeloid leukemia (M2) and smoldering or slowly evolving myeloid leukemia.
Leukemia 1995 Jul
PMID:High degree of myeloid differentiation and granulocytosis is associated with t(8;21) smoldering leukemia. 763 Jan 88

The WT 1 gene has been isolated as a tumor suppressor gene of Wilms' tumor. Using reverse transcriptase-polymerase chain reaction (RT-PCR), relative levels of the WT 1 gene expression was examined in 87 patients with acute leukemia, 25 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma (NHL). Significant levels of the WT 1 gene were expressed in all leukemia patients, and for CML the levels increased as the clinical phase progressed. No point mutations were found in the WT 1 gene when samples from 15 acute leukemia patients were subjected to PCR single-strand conformation polymorphism analysis. In striking contrast to acute leukemia, the levels of WT1 gene expression for NHL were significantly low or even undetectable. The levels of WT 1 gene expression inversely correlated with the prognosis of acute leukemia. The quantification of the WT 1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence of absence of tumor-specific DNA markers. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in four patients (two AML-M3 with PML/RAR-alpha, one AML-M2 with AML1/ETO, and one CML with bcr/abl) detected MRD comparable to that obtained from quantitation of WT 1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT 1 or PML/RAR-alpha gene primers were 10(-3)-10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[WT 1 and leukemia]. 764 50

The very rapid development of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma mow offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is achieved when the DNA sequences amplified are truly leukaemia-specific (i.e. BCR/ABL in CML, PML/RAR-alfa in APL, AML1/ETO in t(8; 21) AML and CBFB/MYH1 in inv(16) AML). A good level of sensitivity may also be achieved by using immunoglobin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. For clinical purposes the crucial issues are the following: can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues are still a matter of debate and several studies are presently in progress to address these points.
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PMID:Minimal residual disease detection in human leukemias: biologic and clinical significance. 765 31

Core binding factor (CBF), also known as polyomavirus enhancer-binding protein 2 and SL3 enhancer factor 1, is a mammalian transcription factor that binds to an element termed the core within the enhancers of the murine leukemia virus family of retroviruses. The core elements of the SL3 virus are important genetic determinants of the ability of this virus to induce T-cell lymphomas and the transcriptional activity of the viral long terminal repeat in T lymphocytes. CBF consists of two subunits, a DNA binding subunit, CBF alpha, and a second subunit, CBF beta, that stimulates the DNA binding activity of CBF alpha. One of the genes that encodes a CBF alpha subunit is AML1, also called Cbf alpha 2. This locus is rearranged by chromosomal translocations in human myeloproliferative disorders and leukemias. An exogenously expressed Cbf alpha 2-encoded subunit (CBF alpha 2-451) stimulated transcription from the SL3 enhancer in P19 and HeLa cells. Activity was mediated through the core elements. Three different isoforms of CBF beta were also tested for transcriptional activity on the SL3 enhancer. The longest form, CBF beta-187, increased the transcriptional stimulation by CBF alpha 2-451 twofold in HeLa cells, although it had no effect in P19 cells. Transcriptional activation by CBF beta required binding to the CBF alpha subunit, as a form of CBF beta that lacked binding ability, CBF beta-148, failed to increase activity. These results indicated that at least in certain cell types, the maximum activity of CBF required both subunits. They also provided support for the hypothesis that CBF is a factor in T lymphocytes that is responsible for recognition of the SL3 cores. We also examined whether CBF could distinguish a 1-bp difference between the enhancer core of SL3 and the core of the nonleukemogenic virus, Akv. This difference strongly affects transcription in T cells and leukemogenicity of SL3. However, no combination of CBF alpha and CBF beta subunits that we tested was able to distinguish the 1-bp difference in transcription assays. Thus, a complete understanding of how T cells recognize the SL3 core remains to be elucidated.
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PMID:Transcriptional activity of core binding factor-alpha (AML1) and beta subunits on murine leukemia virus enhancer cores. 770 14

Chromosomal rearrangements involving band 12p13 are found in a wide variety of human leukemias but are particularly common in childhood acute lymphoblastic leukemia. The genes involved in these rearrangements, however, have not been identified. We now report the cloning of a t(12;21) translocation breakpoint involving 12p13 and 21q22 in two cases of childhood pre-B acute lymphoblastic leukemia, in which t(12;21) rearrangements were not initially apparent. The consequence of the translocation is fusion of the helix-loop-helix domain of TEL, an ETS-like putative transcription factor, to the DNA-binding and transactivation domains of the transcription factor AML1. These data show that TEL, previously shown to be fused to the platelet-derived growth factor receptor beta in chronic myelomonocytic leukemia, can be implicated in the pathogenesis of leukemia through its fusion to either a receptor tyrosine kinase or a transcription factor. The TEL-AML1 fusion also indicates that translocations affecting the AML1 gene can be associated with lymphoid, as well as myeloid, malignancy.
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PMID:Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. 776 24

A novel cell line SKNO-1 was established from the bone marrow cells of a 22-year-old male suffering from acute myeloblastic leukaemia (AML) M2 with t(8;21) whose disease became resistant to chemotherapy after acquisition of 17 monosomy. SKNO-1 has been maintained for more than 36 months as a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent line. Morphologically, SKNO-1 cells were myeloblasts somewhat matured. The cells grow in suspension with a doubling time of 48-72 h. The survival and growth of SKNO-1 cells was absolutely dependent on granulocyte-macrophage colony stimulating factor (GM-CSF). SKNO-1 cells possessed t(8;21) and monosomy 17 which were observed in original leukaemic cells. We confirmed that the AML1 gene, located on chromosome 21, was rearranged and the AML1-MTG8 fusion transcript was expressed in SKNO-1 cells. Over-expression and mutation of the p53 gene were also detected in SKNO-1. It is likely that alterations of AML1 or MTG8 gene and p53 gene contribute to a disease progression in this case. Since t(8;21) translocation is a common chromosome abnormality in AML, and inactivation of the p53 gene may play a crucial role in disease progression in AML, SKNO-1 would be a useful tool for analysing the molecular mechanisms in myeloid leukaemogenesis.
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PMID:Establishment of a myeloid leukaemic cell line (SKNO-1) from a patient with t(8;21) who acquired monosomy 17 during disease progression. 777 16

Fluorescence in situ hybridization (FISH) and/or RNA-based polymerase chain reaction (RT-PCR) were used to analyze the breakpoints within the AML1 gene and the AML1 fusion transcripts in t(8;21) acute myeloid leukemia (AML). Twenty-two patients presented with the simple t(8;21)(q22;q22) and one with a complex variant t(8;2;16;21). In eight cases we used FISH with AML1 cosmid probes on metaphase chromosomes as well as RT-PCR to detect the junctions of MAL1/CDR (ETO,MTG8). Five cases were analyzed by FISH alone and ten cases by RT-PCR alone. By FISH we could identify three groups according to the distribution of the fluorescent signal. Signals were found in group 1 on chromosomes 21 and 21q+, in group 2 on chromosomes 21, 21q+ and 8q- and in group 3 on chromosomes 21 and 8q-. In all groups we could detect an identical AML1/CDR fusion transcript. This transcript showed splicing of AML1 exon 5 onto CDR. Thus regardless of the heterogeneity suggested by FISH, all the breakpoints in the AML1 gene were clustered in the same intro between exons 5 and 6. Our results bring to over one hundred the number of t(8;21) cases in which an identical translocation could be detected at molecular level by RT-PCR. The high sensitivity of the technique makes it suitable for the diagnosis of this translocation in different stages of the disease. The impact of the molecular detection of t(8;21) cells in clinical remission as far as the treatment and the management of the disease are concerned deserves further discussion.
Leukemia 1995 Feb
PMID:Identical fusion transcript associated with different breakpoints in the AML1 gene in simple and variant t(8;21) acute myeloid leukemia. 786 65

The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine relative levels of WT1 gene expression (defined in K562 cells as 1.00) in 45 patients with acute myelogenous leukemia (AML), 22 with acute lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AMLL), 23 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma. Significant levels of WT1 gene were expressed in all leukemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia, the levels of WT1 gene expression for NHL were significantly lower or even undetectable. Clear correlation was observed between the relative levels of WT1 gene expression (< 0.6 v > or = 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), disease-free survival, and overall survival than those with > or = 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 gene expression. The quantitation of the WT1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Continuous monitoring of the WT1 mRNA was performed for 9 patients with acute leukemia. In 4 patients, MRD was detected 2 to 8 months before clinical relapse became apparent. In 2 other patients, the WT1 mRNA gradually increased after discontinuation of chemotherapy. No MRD was detected in the remaining 3 patients with AML who received intensive induction and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PML/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detected MRD comparable with that obtained from quantitation of WT1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic leukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia.
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PMID:WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. 794 79

A large number of AML cases is reviewed in order to clarify biological characteristics of t(8;21) AML cells. The incidence of positivities for stem cell antigens, CD34 and HLA-DR, on blasts in t(8;21) AML is higher in comparison with those in other M2 or M3 categories. Frequent expression of CD34 and HLA-DR is indicative of the stem cell derivation of t(8;21) AML cells. The non-blastic leukemic cells in t(8;21) AML tend to lose the immature phenotype with discordant maturation such as low CD33 expression. Further, the blasts show frequent expression of the B-cell antigen, CD19, without other B-cell antigens and immunoglobulin gene rearrangements. AML cells with t(8;21) showed poorer response to granulocyte-macrophage colony-stimulating factor (GM-CSF) due to a decreased number of GM-CSF binding sites. The absence of monocytic differentiation in t(8;21) AML cells might represent the abnormal response to growth factors at the bifurcation stage of granulocyte and monocyte differentiation. Recently, breakpoint region genes for the 8;21 translocation in chromosome 8 and 21 have been isolated, 48-50 and have been named AML1 and ETO, respectively. The AML1 gene showed a strong homology with the Drosophila segmentation gene, runt, which is thought to be necessary for the Sex lethal gene expression. Since the GM-CSF receptor alpha chain gene locates in the pseudoautosomal region of the sex chromosome, the decrease of GM-CSF binding sites might be related to the AML1/ETO fusion gene expression. Further molecular genetic investigations of the breakpoint genes in the future are expected to clarify the unique biological events seen in this type of leukemia.
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PMID:Cellular characteristics of acute myeloblastic leukemia associated with t(8;21)(q22;q22). The Japanese Cooperative Group of Leukemia/Lymphoma. 804 46


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