Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The t(3;21) (q26;q22) chromosomal translocation associated with blastic crisis of chronic myelogenous leukemia (CML) results in the formation of a chimeric protein fusing the amino-terminal DNA-binding domain encoded by the AML1 gene to the carboxyl-terminal-encoding portion of the Evi-1 gene. In order to evaluate transforming activity of this protein, AML1/Evi-1 was introduced into Rat1 fibroblasts. Cells expressing the fusion product formed macroscopic colonies in soft agar, indicating that AML1/Evi-1 is a transforming gene. It was also demonstrated that introduction of AML1/Evi-1 into the Rat1 clones harboring BCR/ABL also conferred enhanced capacity for anchorage independent growth. Analyses of deletion mutants of AML1/Evi-1 revealed that removal of the second zinc finger domain within the Evi-1 sequence totally abrogated the ability of AML1/Evi-1 to transform Rat1 cells. We showed that the transforming effect is correlated with the AP-1 activation induced by AML1/Evi-1. Furthermore, we demonstrated that c-jun is transcriptionally activated in Rat1 cells transformed by AML1/Evi-1, suggesting that c-jun expression is under control of AML1/Evi-1. These results indicate that the oncogenic effect of the t(3;21) translocation is caused by the generation of a chimeric transcriptional factor and that AML1/Evi-1 could perform a pivotal role in leukemic progression of CML.
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PMID:The AML1/Evi-1 fusion protein in the t(3;21) translocation exhibits transforming activity on Rat1 fibroblasts with dependence on the Evi-1 sequence. 767 44

Evi-1 is a transforming gene originally identified in a common integration site of murine leukemia retrovirus and mapped in human chromosome 3q26. It is not normally expressed in either human or murine hematopoietic cells, but is overexpressed in retrovirus-induced murine myeloid leukemias as well as human myeloid leukemias with 3q26 abnormalities, and thus thought to be responsible for both human and murine leukemogenesis. In this study, possible involvement of the Evi-1 gene in human leukemias was evaluated by Northern blot analysis in a total of 73 patients with various types of leukemias. We found that increased expression of the Evi-1 gene was most frequently observed in patients with CML in blastic crisis. It was found in 10 of 14 (71.0%) samples from CML in blastic crisis, three of 15 (20.0%) from acute myelocytic leukemia, three of 11 (27.3%) from MDS-derived leukemia, and one of 11 (9.1%) from acute lymphoblastic leukemia. Among 18 patients showing increased Evi-1 expression, none of 17 informative patients showed cytogenetic abnormalities involving 3q26. In addition, Southern blot analysis revealed neither amplification nor rearrangements of the Evi-1 gene in 11 Evi-1-positive patients whose DNA samples were available. Our results suggest that increased expression of the Evi-1 gene may play an important role in development of human leukemias, especially in progression from chronic phase to blastic crisis of CML even without 3q26 abnormalities.
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PMID:Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia. 865 73

The human Evi-1 gene located on chromosome 3q26, encodes a zinc finger protein that functions as a transcription factor. It was frequently overexpressed in leukemias having 3q26 abnormalities such as t(3;3)(q21;q26) and inv(3)(q21 q26), and subjected to structural alteration in t(3;21)(q26;q22). In addition, recent studies indicated that several cases of leukemias without 3q26 abnormalities also expressed Evi-1 gene. In this study we present another case of structural alteration of Evi-1 gene in a case of inv(3)(q21 q26), in which Evi-1 was truncated and a shorter form of Evi-1 protein was expressed upon rearrangement of the gene. We also studied expression of the Evi-1 gene in a variety of leukemias by northern blot analysis. Evi-1 was overexpressed not only in leukemias with 3q26 abnormalities, but, in those without 3q26 abnormalities, especially in blast crisis of CML. Our result also supports an idea that Evi-1 is a relevant oncogene whose overexpression or structural changes might play a crucial role in development of human leukemias.
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PMID:Abnormal expression of Evi-1 gene in human leukemias. 918 65

Activation of the Evi-1 gene was first described to be associated with the transformation of murine myeloid leukaemias and has previously been detected in cases of human acute myeloid leukaemia (AML) and chronic myeloid leukaemia (CML) in blast crises and in myelodysplastic syndromes. In this study we determined the frequency and the level of Evi-1 expression in juvenile myelomonocytic leukaemia (JMML) and in normal haemopoiesis. Using RT-PCR and Southern blot hybridization mRNA of Evi-1 could be detected in bone marrow (BM) and peripheral blood (PB) mononuclear cells (MNC) of normal donors. In JMML 12/20 patients examined expressed elevated levels of Evi-1 compared to normal controls. In these samples over-expression of the gene was correlated with a higher percentage of blasts (P = 0.02). Expression levels in BFU-E and CFU-GM derived colonies from BM of JMML patients were lower than those in the corresponding MNC samples. Analysis of CD34+ and CD34- cells demonstrated that Evi-1 is primarily expressed in the CD34+ cell population of both JMML and normal donors. These findings suggest that Evi-1 expression is linked to the early stages of haemopoiesis. Studies on the regulation of Evi-1 expression in CD34+ cells will elucidate its function in progenitor cells and clarify its possible role in the pathogenesis of JMML.
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PMID:Expression of the Evi-1 gene in haemopoietic cells of children with juvenile myelomonocytic leukaemia and normal donors. 943 37

The t(3;21)(q26;q22) chromosomal translocation associated with blastic crisis of chronic myelogenous leukemia results in the formation of the AML1/Evi-1 chimeric protein, which is thought to play a causative role in leukemic transformation of hematopoietic cells. Here we show that AML1/Evi-1 represses growth-inhibitory signaling by transforming growth factor-beta (TGF-beta) in 32Dcl3 myeloid cells. The activity of AML1/Evi-1 to repress TGF-beta signaling depends on the two separate regions of the Evi-1 portion, one of which is the first zinc finger domain. AML1/Evi-1 interacts with Smad3, an intracellular mediator of TGF-beta signaling, through the first zinc finger domain, and represses the Smad3 activity, as Evi-1 does. We also show that suppression of endogenous Evi-1 in leukemic cells carrying inv(3) restores TGF-beta responsiveness. Taken together, AML1/Evi-1 acts as an inhibitor of TGF-beta signaling by interfering with Smad3 through the Evi-1 portion, and both AML1/Evi-1 and Evi-1 repress TGF-beta-mediated growth suppression in hematopoietic cells. Thus, AML1/Evi-1 may contribute to leukemogenesis by specifically blocking growth-inhibitory signaling of TGF-beta in the t(3;21) leukemia.
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PMID:The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-beta-mediated growth inhibition of myeloid cells. 983 2

Chronic myelogenous leukemia is a stem cell tumor characterized by the t(9; 22)(q34; 11) translocation generating the BCR/ABL chimeric gene. The BCR/ABL fusion gene shows several functions, including inhibition of adhesion to stroma cells and extracellular matrix, activation of mitogenic signalings, inhibition of apoptosis, and degradation of inhibitory proteins, and thereby causes transformation of hematopoietic progenitors. Among its functions, the signal transduction pathways activated by the fusion gene are Ras and MAP kinase pathways, Jak-Stat pathways, PI3 kinase pathways, and Myc pathways. Molecular mechanisms in blastic crisis remains largely unknown. However, loss of functions of tumor suppressor genes such as p53, RB, and p16, activation of oncogene Ras, overexpression of Evi-1 might be involved in disease progression.
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PMID:[Disease-related gene and tumor progression]. 1176 32

AML1/Evi-1 is a chimeric protein that is derived from t(3;21), found in blastic transformation of chronic myelogenous leukemia. It is composed of the N-terminal AML1 portion with the DNA-binding Runt domain and the C-terminal Evi-1 portion. It has been shown to dominantly repress AML1-induced transactivation. The mechanism for it has been mainly attributed to competition with AML1 for the DNA-binding and for the interaction with PEBP2beta (CBFbeta), a partner protein which heterodimerizes with AML1. It was recently found that Evi-1 interacts with C-terminal binding protein (CtBP) to repress TGFbeta-induced transactivation. Here, we demonstrate that AML1/Evi-1 interacts with CtBP in SKH1 cells, a leukemic cell line which endogenously overexpresses AML1/Evi-1 and that AML1/Evi-1 requires the interaction with CtBP to repress AML1-induced transactivation. The association with CtBP is also required when AML1/Evi-1 blocks myeloid differentiation of 32Dcl3 cells induced by granulocyte colony-stimulating factor. Taken together, it is suggested that one of the mechanisms for AML1/Evi-1-associated leukemogenesis should be an aberrant recruitment of a corepressor complex by the chimeric protein.
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PMID:The t(3;21) fusion product, AML1/Evi-1 blocks AML1-induced transactivation by recruiting CtBP. 1196 42

The t(3;21) chromosomal translocation seen in blastic crisis of chronic myeloid leukemia and secondary leukemias results in a formation of a chimeric protein AML1-Evi-1, which suppresses wild-type AML1 function. Loss of AML1 function causes expansion of hematopoietic progenitor cells, whereas it is not sufficient for the development of leukemia. To identify essential mechanisms through which AML1-Evi-1 exerts full leukemogenic potential, we introduced AML1-Evi-1 and its mutants in murine bone marrow cells, and evaluated their transforming activities by colony replating assays. The transforming activity of AML1-Evi-1 was lost when any of the known functional domains of Evi-1 was deleted from the chimeric protein, and forced expression of Evi-1 did not transform the AML1-deleted bone marrow cells. Unlike the MLL-ENL and AML1-ETO leukemia-related chimeric proteins, AML1-Evi-1 could transform only the hematopoietic stem cell fraction. Moreover, AML1-Evi-1-transformed cells show a cell-marker profile distinct from that of the cells transformed by AML1-ETO, which also suppresses AML1 function. Thus, leukemogenic activity of AML1-Evi-1 may be due to activation of molecular mechanisms distinct from those activated by MLL-ENL or AML1-ETO in the hematopoietic stem cell fractions.
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PMID:AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1. 1833 62