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

EVI1 is a zinc finger oncoprotein that binds via fingers 1-7 to the sequence GACAAGATAA. The target genes on which EVI1 acts are unknown. This binding motif overlaps with that for the GATA transcription factors, (T/A)GATA(A/G), and GATA-1 can bind to and activate transcription via a GACAAGATAA motif. The possibility has been raised that, when overexpressed in leukemogenesis, EVI1 may function by interfering with the differentiation-promoting action of GATA factors. To explore this, we have assessed the affinity of EVI1 for the GATA binding sites derived from erythroid-specific GATA-1 target genes, and found only low affinity interactions. We examined the contacts between EVI1 and DNA by methylation interference studies, which revealed extensive contacts between EVI1 and its binding site. The importance of the contacts for high affinity binding was shown by in vitro quantitative gel shift studies and in vivo cotransfection studies. To examine what types of sequences from mouse genomic DNA bind to EVI1, we isolated and sequenced five EVI1-binding fragments, and each showed the GACAAGATA site. The data presented contribute to our knowledge of the binding specificity of EVI1, and yield a clearer picture of what sequences can, and cannot, act as targets for EVI1 action.
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PMID:Zinc fingers 1-7 of EVI1 fail to bind to the GATA motif by itself but require the core site GACAAGATA for binding. 855 37

Through chromosomal rearrangements and/or proviral insertions, a number of genes encoding nuclear transcription factors have been identified that play key roles in leukemogenesis. One of these is Evi1, which plays a role in both murine and human myeloid leukemia. The exact mechanism by which Evi1 exerts its leukemogenic effect is not clear, but it may involve the inhibition of terminal differentiation, through the abnormal repression of genes necessary for cellular maturation. Our analysis of the DNA binding characteristics of EVI1 indicate a high degree of specificity, which likely indicates that the protein acts on a tightly defined number of targets in the cell. We are beginning to characterize candidate target genes located in the mouse genome near EVI1 binding sites with the expectation that these will yield insight into EVI1 function both in normal cells and in leukemogenesis.
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PMID:Molecular analysis of Evi1, a zinc finger oncogene involved in myeloid leukemia. 858 52

A novel human leukemia cell line (Kasumi-3) was established from the blast cells of a 57-year-old man suffering from myeloperoxidase-negative acute leukemia. The cell line had five distinctive features, as follows. 1) Flow cytometric analyses showed cell surface expression of CD7, CD4, CD13, CD33, CD34, HLA-DR and c-Kit. This phenotype is compatible with that of acute myelocytic leukemia cells with the M0 subtype in the French-American-British classification. 2) Kasumi-3 cells carried chromosomal abnormalities of t(3;7)(q27:q22), del(5)(q15), del(9)(q32), and add(12)(p11). The breakpoint of 3q27 was located near the EVI1 gene, and a high level of expression of the EVI1 gene was observed. 4) Kasumi-3 cells treated with TPA showed maturation to monocytic lineage. 5) Treatment with either interleukin (IL)-2, IL-3, IL-4, granulocyte-macrophage colony-stimulating or stem cell factor induced the proliferation of Kasumi-3 cells. Thus, the Kasumi-3 cell line shows the characteristic features of undifferentiated leukemia. It should, therefore, be useful both for studying the biological characteristics of acute myelogenous leukemia M0 subtype and for investigating the role of the EVI1 gene in leukemogenesis.
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PMID:Establishment of an undifferentiated leukemia cell line (Kasumi-3) with t(3;7)(q27;q22) and activation of the EVI1 gene. 861 29

The t(12;21) (p13;q22) is observed in approximately 20-25% of childhood B-lineage acute lymphoblastic leukemia (ALL) cases in both Asian and Caucasian populations. This translocation results in the fusion of TEL, a recently described ETS-like gene on 12p13, and AML1, which was shown to be involved in the formation of fusion genes with ETO and EVI1 in myeloid leukemias. Fluorescence in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis are useful in detecting this translocation which is not readily identified with routine cytogenetic techniques. The t(12;21) is associated with a distinct subgroup of patients characterized by an age between 1 and 10 years, an early B immunophenotype, and a good prognosis. A high incidence of the deletion of non-translocated TEL is another characteristic of leukemic cells with this translocation. TEL-AML1 hybrid protein thought to be critical in leukemogenesis possesses the HLH domain of TEL fused to almost the entire AML1 protein, although the detailed mechanisms of leukemogenesis remain obscure. RT-PCR combined with FISH analysis of posttreatment samples appears to be useful in detecting early relapse or minimal residual disease and thus, is expected to optimize the treatment strategy for patients with t(12;21).
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PMID:Detection of the Der (21)t(12;21) chromosome forming the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia. 949 2

Chromosomal translocation often results in aberrant activation of the genes with oncogenic potential and, thus, plays an important role in leukemogenesis. We report a unique case of acute myelomonocytic leukemia carrying a rare reciprocal translocation, t(3;12)(q26;p13). This patient displayed typical clinical features of 3q21q26 syndrome such as abnormal thrombopoiesis and rapid disease progression. Blastic cells from the patient strongly expressed the EVI1 gene, which is located on 3q26 and is normally suppressed in bone marrow cells. Expression of the TEL gene, located on 12p13, was also observed, but fusion transcript between two genes was not found. No structural alterations of the EVI1 and TEL genes were detected by Southern blot and PCR analyses. We reviewed previous literature and found 10 other cases with t(3;12)(q26;p13). These patients comprise a unique disease group with features including dyshematopoiesis and poor prognosis. However, characteristics related to 3q21q26 syndrome were observed only in the present case. Further investigation is required to elucidate the molecular basis of this particular entity.
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PMID:A novel variant of acute myelomonocytic leukemia carrying t(3;12)(q26;p13) with characteristics of 3q21q26 syndrome. 969 9

The AML1 and CBFbeta subunits of core binding factor (CBF) are involved in several chromosomal abnormalities frequently associated with acute leukemias. As a result, the CBFbeta-SMMHC, AML1-ETO and AML1-MDS1/EVI1 fusion proteins are expressed in subsets of acute myeloid leukemia, and TEL-AML1 is expressed in B-lineage acute lymphocytic leukemia. These CBF oncoproteins likely contribute to leukemogenesis in part by inhibiting endogenous CBF. As a result they are expected to inhibit differentiation and perhaps apoptosis. In addition, the domains unique to each fusion protein may also contribute to leukemogenesis via unique mechanisms.
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PMID:Leukemogenesis by CBF oncoproteins. 1060 13

The human t(3;21)(q26;q22) translocation is found as a secondary mutation in some cases of chronic myelogenous leukemia during the blast phase and in therapy-related myelodysplasia and acute myelogenous leukemia. One result of this translocation is a fusion between the AML1, MDS1, and EVI1 genes, which encodes a transcription factor of approximately 200 kDa. The role of the AML1/MDS1/EVI1 (AME) fusion gene in leukemogenesis is largely unknown. In this study, we analyzed the effect of the AME fusion gene in vivo by expressing it in mouse bone marrow cells via retroviral transduction. We found that mice transplanted with AME-transduced bone marrow cells suffered from an acute myelogenous leukemia (AML) 5-13 mo after transplantation. The disease could be readily transferred into secondary recipients with a much shorter latency. Morphological analysis of peripheral blood and bone marrow smears demonstrated the presence of myeloid blast cells and differentiated but immature cells of both myelocytic and monocytic lineages. Cytochemical and flow cytometric analysis confirmed that these mice had a disease similar to the human acute myelomonocytic leukemia. This murine model for AME-induced AML will help dissect the molecular mechanism of AML and the molecular biology of the AML1, MDS1, and EVI1 genes.
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PMID:Human AML1/MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a model for human AML. 1067 31

The development of acute myelogenous leukemia (AML), which is characterized by a block of myeloid differentiation, is a multi-step process that involves several genetic abnormalities, but the molecular mechanisms by which these genetic alterations cooperate in leukemogenesis are poorly understood. The human chronic myelogenous leukemia (CML) is a model for multi-step leukemogenesis. BCR-ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR-ABL efficiently induces a myeloproliferative disorder (MPD) in mice, but progression to CML blast phase requires additional mutations. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase. We have previously shown that AME can induce an AML in mice but with a greatly extended latency, suggesting a requirement for additional mutations. Here we demonstrate that AME alone does not block myeloid differentiation in vivo during the 4-month pre-leukemia stage, yet co-expression of BCR-ABL and AME in mice can block myeloid differentiation and rapidly induce an AML. Our results suggest that block of myeloid differentiation and induction of AML involves cooperation between mutations that dysregulate protein tyrosine kinase signaling and those that disrupt hematopoietic gene transcription.
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PMID:Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. 1178 38

One of the genes associated with both murine and human myeloid leukemia is EVI1 (ecotropic viral integration 1 site). EVI1 was first identified as a common locus of retroviral integration in myeloid tumors found in AKXD mice. The exact mechanism by which EVI1 induces leukemogenesis is not clear. Studies of the function of EVI1 in the bone marrow and in cell lines have shown that the inappropriate expression of EVI1 prohibits terminal differentiation of the bone marrow progenitor cells in granulocytes and erythroid cells, but strongly favors hematopoietic differentiation along the megakaryocytic lineage. We summarize recent data showing that EVI1 is a complex transcription factor with multiple functions, and this complexity is further demonstrated by the ability of EVI1 to interact with coactivators and corepressors and to abrogate cellular response to cytokines.
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PMID:The role of EVI1 in normal and leukemic cells. 1297 28

Patients with myeloid malignancies and either the 3q21q26 syndrome or t(1;3)(p36;q21) have been reported to share similar clinicopathological features and a common molecular mechanism for leukemogenesis. Overexpression of MDS1/EVI1 (3q26) or MEL1/PRDM16 (1p36), both members of the PR-domain family, has been directly implicated in the malignant transformation of this subset of neoplasias. The breakpoints in both entities are outside the genes, and the 3q21 region, where RPN1 is located, seems to act as an enhancer. MEL1 has been reported to be expressed in leukemia cells with t(1;3) and in the normal uterus and fetal kidney, but neither in bone marrow (BM) nor in other tissues, suggesting that this gene is specific to t(1;3)-positive MDS/AML. We report the molecular characterization of a t(1;3)(p36;q21) in a patient with MDS (RAEB-2). In contrast to previous studies, we demonstrate that MEL1, the PR-containing form, and MEL1S, the PR-lacking form, are widely expressed in normal tissues, including BM. The clinicopathological features and the breakpoint on 1p36 are different from cases previously described, and MEL1 is not overexpressed, suggesting a heterogeneity in myeloid neoplasias with t(1;3).
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PMID:Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells. 1471 37


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