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)

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 leukemia-associated fusion gene AML1/MDS1/EVI1 (AME) encodes a chimeric transcription factor that results from the (3;21)(q26;q22) translocation. This translocation is observed in patients with therapy-related myelodysplastic syndrome (MDS), with chronic myelogenous leukemia during the blast crisis (CML-BC), and with de novo or therapy-related acute myeloid leukemia (AML). AME is obtained by in-frame fusion of the AML1 and MDS1/EVI1 genes. We have previously shown that AME is a transcriptional repressor that induces leukemia in mice. In order to elucidate the role of AME in leukemic transformation, we investigated the interaction of AME with the transcription co-regulator CtBP1 and with members of the histone deacetylase (HDAC) family. In this report, we show that AME physically interacts in vivo with CtBP1 and HDAC1 and that these co-repressors require distinct regions of AME for interaction. By using reporter gene assays, we demonstrate that AME represses gene transcription by CtBP1-dependent and CtBP1-independent mechanisms. Finally, we show that the interaction between AME and CtBP1 is biologically important and is necessary for growth upregulation and abnormal differentiation of the murine hematopoietic precursor cell line 32Dc13 and of murine bone marrow progenitors.
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PMID:The leukemia-associated transcription repressor AML1/MDS1/EVI1 requires CtBP to induce abnormal growth and differentiation of murine hematopoietic cells. 1208 39

RUNX1-EVI1 is a chimeric gene generated by t(3;21)(q26;q22) observed in patients with aggressive transformation of myelodysplastic syndrome or chronic myelogenous leukemia. RUNX1-EVI1 has oncogenic potentials through dominant-negative effect over wild-type RUNX1, inhibition of Jun kinase (JNK) pathway, stimulation of cell growth via AP-1, suppression of TGF-beta-mediated growth inhibition and repression of C/EBPalpha. Runx1-EVI1 heterozygous knock-in mice die in uteri due to central nervous system (CNS) hemorrhage and severe defects in definitive hematopoiesis as Runx1-/- mice do, indicating that RUNX1-EVI1 dominantly suppresses functions of wild-type RUNX1 in vivo. Acute myelogenous leukemia is induced in mice transplanted with bone marrow cells expressing RUNX1-EVI1, and a Runx1-EVI1 knock-in chimera mouse developed acute megakaryoblastic leukemia. These results suggest that RUNX1-EVI1 plays indispensable roles in leukemogenesis of t(3;21)-positive leukemia. Major leukemogenic effect of RUNX1-EVI1 is mainly through histone deacetyltransferase recruitment via C-terminal binding protein. Histone deacetyltransferase could be a target in molecular therapy of RUNX1-EVI1-expressing leukemia.
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PMID:Role of the RUNX1-EVI1 fusion gene in leukemogenesis. 1901 45

Transforming growth factor beta 1 (TGF-beta1) is the prototypic member of a large family of structurally related pleiotropic-secreted cytokines. The TGF-beta1/SMAD signaling pathway usually participates in a wide range of cellular processes such as growth, proliferation, differentiation and apoptosis. Upon binding on TGF-beta1, the dimerized TGF-beta type II receptors recruit and phosphorylate the TGF-beta type I receptors, which phosphorylate the receptor-regulated SMAD (SMAD2 and SMAD3) presented by the SMAD anchor for receptor activation. The phosphorylated receptor-regulated SMAD form heterologous complexes with the common-mediator SMAD (SMAD4) and subsequently translocate into the nucleus, where they interact with other transcription factors to regulate the expression of target genes. This multi-functional signaling pathway modulated by various elements with complex mechanisms at different levels is also inevitably involved in cancer. We herein present data on the role of the TGF-beta1/SMAD signaling pathway in human chronic myeloid leukemia and explain the potent biological effects of TGF-beta1 on leukemia cells. The paper is based on a review of articles selected from Cancerline and Medline data bases. The constitutively active tyrosine kinase produced by the specific Bcr-Abl fusion gene on the Philadelphia chromosome can enhance the resistance of malignant cells to TGF-beta1-induced growth inhibition and apoptosis, which contributes to enhancement of proteasomal degradation of p27. However, overexpression of the EVI1 gene, which is also caused by Bcr-Abl, can recruit the C-terminal binding protein and histone deacetylase to prevent the MH2 domain on SMAD3. The later is essential for transcription activation on target genes and leads to blockage of the TGF-beta1/SMAD signaling pathway. Some studies have indicated that certain therapeutic agents applied in clinical treatment can inhibit proliferation and promote differentiation of leukemia cells by way of modulation of the TGF-beta1/SMAD signal pathway. For example, arsenic trioxide can promote specific degradation of the AML1/MDS1/EVI1 oncoprotein and inhibit the proliferation of leukemia cells. However, specific histone deacetylase inhibitors can interrupt the effect of histone deacetylase to alleviate EVI1-mediated suppression of TGF-beta1/SMAD signaling. The tyrosine kinase inhibitor in the target therapy of chronic myeloid leukemia can effectively inhibit the tyrosine kinase activity of Bcr-Abl and induce suppression on the TGF-beta1/SMAD signaling pathway. The TGF-beta1/SMAD signaling pathway plays an important role in chronic myeloid leukemia cells and leads the leukemia cells to growth inhibition, differentiation and apoptosis. The positive influence of the TGF-beta1/SMAD signaling pathway in chronic myeloid leukemia is fairly significant, and its potential effects in clinical treatment will bring about definite benefits. Since it is a complex signaling pathway widely involved in many aspects of cellular activities, further study and comprehensive analysis of the TGF-beta1/SMAD signaling pathway are imperative and will have a guiding significance in research and clinical applications. It is an exciting area for future research.
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PMID:The transforming growth factor beta 1/SMAD signaling pathway involved in human chronic myeloid leukemia. 2130 8