scholarly journals Expression of Evi-1 Gene in Leukaemia: Diagnostic and Prognostic Perspective

2021 ◽  
pp. 121-135
Author(s):  
Ifeyinwa Maryann Okafor ◽  
Henshaw Uchechi Okoroiwu
Keyword(s):  
Zinc Finger ◽  
Cancer Progression ◽  
Integration Site ◽  
White Blood Cells ◽  
Ectopic Expression ◽  
Genetic Mutation ◽  
Biochemical Properties ◽  
Terminal Region ◽  
Malignant Neoplasms ◽  
Zinc Finger Domains

Leukaemias are malignant neoplasms characterized by disorderly, purposeless proliferation of white blood cells with abundance of one cell type. The exact aetiology of leukaemias is still yet to be fully understood. However, it is generally believed that neoplasm is caused by genetic mutation, chromosomal translocation, or activation of certain oncogenes. There are also nuclear oncogenes which are also vital genes in normal cell proliferation and differentiation, often being pivotal genes in developmental and cell cycle regulation. They are also important in cancer progression. Ecotropic viral integration site (EVI-1), a nuclear oncogene has been implicated in the progression of some leukaemias. EVI-1 gene is located on the human chromosome 3 band q24-q28 and spans over 100 kb.  The EVI-1 gene encodes a 145 kDa protein of the zinc-finger family which is an essential transcription factor for appropriate murine and human development and is also associated with some leukaemias, following ectopic expression. EVI-1 protein is divided into two main regions: The N-terminal region that contains zinc finger domains (ZFi) and C-terminal region containing three zinc finger domains (ZFii) and a sequence of acidic amino acid. This review summarizes the biological, leukaemogenetic/oncogenic roles and biochemical properties of EVI-1. It further discusses the diagnostic and prognostic implication of EVI-1 in some leukaemias, encouraging incorporation of routine assay of EVI-1 in diagnosis and prognostic monitoring of leukaemias.

Identification of the Genomic Breakpoints at 1p36.3 and 3q21.3 in Five MDS/AML(M4) Patients with t(1;3)(p36;q21) Translocation. GATA2 Mutation May Be Involved in Leukemogenesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2899-2899
Author(s):  
Phan Thi Xinh ◽  
Hoang Anh Vu ◽  
Fumitoshi Taketazu ◽  
Shin Fujisawa ◽  
Hideo Tanaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Zinc Finger ◽  
Bone Marrow Cells ◽  
Expression Patterns ◽  
Ectopic Expression ◽  
Large Deletion ◽  
Rt Pcr ◽  
First Intron ◽  
Zinc Finger Domains ◽  
Marrow Cells

Abstract Reciprocal translocation t(1;3)(p36;q21) is found in a subset of MDS/AML characterized by trilineage dysplasia, especially dysmegakaryopoiesis and a poor prognosis. In this leukemia, ectopic expression of MEL1 at 1p36.3 driven by the promoter of RPN1 at 3q21 is thought to be associated with the pathogenesis. Recently, we reported the identification of 2 kinds of the 1p36 breakpoint (BP) region in 3 patients with t(1;3), 1) a 70.7-kb region within the first intron of MEL1 in one patient, and 2) a 29.2-kb region in the 5′ region of MEL1 in the remaining two. However, the precise BP at 3q21 has not yet been determined. Here, we report that we have defined the 3q21 BP in 4 patients, and the 1p36.3 BP in 2 additional patients with FISH using bone marrow cells obtained from 4 patients (4 with MDS-related AML-M4 and one with CMML). To identify the BPs and deletions at 1p36.3 or at 3q21.3, we used 18 non-contig BAC/PAC probes and 7 contig BAC/PAC probes, respectively. FISH study revealed that the 3q21 BPs were clustered within RP11-475N22 probe in the 4 patients, in the 5′ region of GATA2. The 1p36.3 BP was found within the first intron of MEL1 in one patient, but in a 68.5-kb region which included a part of the first intron and a region of 5′ site of MEL1 in the other. Therefore, 3 BP regions at 1p36 were found among the 5 patients. No deletions were detected in the vicinity of the 1p36 BP or 3q21 BP in any of our 5 patients, although Lahortiga et al., detected a large deletion at the both BPs in their patients with MDS (RAEB) and t(1;3) (Oncogene 23:311–316, 2004). In Patient 1 (the 1p36 BP was in the first intron of MEL1) and Patient 3 (the 1p36 BP was in 5′ site of MEL1), the expression patterns of MEL1, ARPM2, and GATA2 which are located near the BPs were analyzed with RT-PCR. ARPM2 was not overexpressed in the two patients, while MEL1 was overexpressed in Patient 1, but not in Patient 3 when the expression level was compared with that of normal bone marrow cells. It is reported that GATA2, one of the zinc finger transcription factors, serves as a regulator of genes controlling proliferative capacity of early hematopoietic cells, and that two zinc finger domains of GATA2 are closely involved in inducing megakaryocytic differentiation. Interestingly, a deleted GATA2 transcript was detected in Patient 3 together with a wild type GATA2 transcript. The short GATA2 transcript contained 1009 nucleotides deletion from exon 3 to exon 6 with a frameshift, resulting in lacking the two zinc finger domains. Thus, there is the possibility that dysmegakaryopoiesis in this patient is associated with the expression of GATA2 without the zinc finger domains.

scholarly journals TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
You Shuai ◽  
Zhonghua Ma ◽  
Weitao Liu ◽  
Tao Yu ◽  
Changsheng Yan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Mechanistic Model ◽  
Ectopic Expression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tissue Samples ◽  
Reporter Assays

Abstract Background Gastric cancer (GC) is the third leading cause of cancer-related mortality globally. Long noncoding RNAs (lncRNAs) are dysregulated in obvious malignancies including GC and exploring the regulatory mechanisms underlying their expression is an attractive research area. However, these molecular mechanisms require further clarification, especially upstream mechanisms. Methods LncRNA MNX1-AS1 expression in GC tissue samples was investigated via microarray analysis and further determined in a cohort of GC tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Cell proliferation and flow cytometry assays were performed to confirm the roles of MNX1-AS1 in GC proliferation, cell cycle regulation, and apoptosis. The influence of MNX1-AS1 on GC cell migration and invasion was explored with Transwell assays. A xenograft tumour model was established to verify the effects of MNX1-AS1 on in vivo tumourigenesis. The TEAD4-involved upstream regulatory mechanism of MNX1-AS1 was explored through ChIP and luciferase reporter assays. The mechanistic model of MNX1-AS1 in regulating gene expression was further detected by subcellular fractionation, FISH, RIP, ChIP and luciferase reporter assays. Results It was found that MNX1-AS1 displayed obvious upregulation in GC tissue samples and cell lines, and ectopic expression of MNX1-AS1 predicted poor clinical outcomes for patients with GC. Overexpressed MNX1-AS1 expression promoted proliferation, migration and invasion of GC cells markedly, whereas decreased MNX1-AS1 expression elicited the opposite effects. Consistent with the in vitro results, MNX1-AS1 depletion effectively inhibited the growth of xenograft tumour in vivo. Mechanistically, TEAD4 directly bound the promoter region of MNX1-AS1 and stimulated the transcription of MNX1-AS1. Furthermore, MNX1-AS1 can sponge miR-6785-5p to upregulate the expression of BCL2 in GC cells. Meanwhile, MNX1-AS1 suppressed the transcription of BTG2 by recruiting polycomb repressive complex 2 to BTG2 promoter regions. Conclusions Our findings demonstrate that MNX1-AS1 may be able to serve as a prognostic indicator in GC patients and that TEAD4-activatd MNX1-AS1 can promote GC progression through EZH2/BTG2 and miR-6785-5p/BCL2 axes, implicating it as a novel and potent target for the treatment of GC.

scholarly journals New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 867
Author(s):  
Bruno Oyallon ◽  
Marie Brachet-Botineau ◽  
Cédric Logé ◽  
Thomas Robert ◽  
Stéphane Bach ◽  
...  
Keyword(s):  
Colorectal Carcinoma ◽  
Cancer Progression ◽  
Kinase Inhibitors ◽  
Integration Site ◽  
Leukemia Virus ◽  
Biological Evaluation ◽  
Design Synthesis ◽  
Proviral Integration Site ◽  
Quinoxaline Derivatives

Proviral integration site for Moloney murine leukemia virus (Pim)-1/2 kinase overexpression has been identified in a variety of hematologic (e.g., multiple myeloma or acute myeloid leukemia (AML)) and solid (e.g., colorectal carcinoma) tumors, playing a key role in cancer progression, metastasis, and drug resistance, and is linked to poor prognosis. These kinases are thus considered interesting targets in oncology. We report herein the design, synthesis, structure–activity relationships (SAR) and in vitro evaluations of new quinoxaline derivatives, acting as dual Pim1/2 inhibitors. Two lead compounds (5c and 5e) were then identified, as potent submicromolar Pim-1 and Pim-2 inhibitors. These molecules were also able to inhibit the growth of the two human cell lines, MV4-11 (AML) and HCT-116 (colorectal carcinoma), expressing high endogenous levels of Pim-1/2 kinases.

scholarly journals From cytopenia to leukemia: the role of Gfi1 and Gfi1b in blood formation

Blood ◽  
2015 ◽  
Vol 126 (24) ◽  
pp. 2561-2569 ◽  
Author(s):  
Tarik Möröy ◽  
Lothar Vassen ◽  
Brian Wilkes ◽  
Cyrus Khandanpour
Keyword(s):  
Zinc Finger ◽  
Target Genes ◽  
Integration Site ◽  
Wide Spectrum ◽  
Human Leukemia ◽  
Specific Expression ◽  
Hematopoietic Stem ◽  
Proviral Integration Site ◽  
Cell Type Specific Expression

AbstractThe DNA-binding zinc finger transcription factors Gfi1 and Gfi1b were discovered more than 20 years ago and are recognized today as major regulators of both early hematopoiesis and hematopoietic stem cells. Both proteins function as transcriptional repressors by recruiting histone-modifying enzymes to promoters and enhancers of target genes. The establishment of Gfi1 and Gfi1b reporter mice made it possible to visualize their cell type–specific expression and to understand their function in hematopoietic lineages. We now know that Gfi1 is primarily important in myeloid and lymphoid differentiation, whereas Gfi1b is crucial for the generation of red blood cells and platelets. Several rare hematologic diseases are associated with acquired or inheritable mutations in the GFI1 and GFI1B genes. Certain patients with severe congenital neutropenia carry mutations in the GFI1 gene that lead to the disruption of the C-terminal zinc finger domains. Other mutations have been found in the GFI1B gene in families with inherited bleeding disorders. In addition, the Gfi1 locus is frequently found to be a proviral integration site in retrovirus-induced lymphomagenesis, and new, emerging data suggest a role of Gfi1 in human leukemia and lymphoma, underlining the role of both factors not only in normal hematopoiesis, but also in a wide spectrum of human blood diseases.

scholarly journals Bivalent Genes Targeting of Glioma Heterogeneity and Plasticity

2021 ◽  
Vol 22 (2) ◽  
pp. 540
Author(s):  
Mariam Markouli ◽  
Dimitrios Strepkos ◽  
Kostas A. Papavassiliou ◽  
Athanasios G. Papavassiliou ◽  
Christina Piperi
Keyword(s):  
Gene Expression ◽  
Cancer Progression ◽  
Integration Site ◽  
Survival Rates ◽  
Family Members ◽  
Therapy Resistance ◽  
Cellular Functions ◽  
Cns Neoplasms ◽  
Development Regulation

Gliomas account for most primary Central Nervous System (CNS) neoplasms, characterized by high aggressiveness and low survival rates. Despite the immense research efforts, there is a small improvement in glioma survival rates, mostly attributed to their heterogeneity and complex pathophysiology. Recent data indicate the delicate interplay of genetic and epigenetic mechanisms in regulating gene expression and cell differentiation, pointing towards the pivotal role of bivalent genes. Bivalency refers to a property of chromatin to acquire more than one histone marks during the cell cycle and rapidly transition gene expression from an active to a suppressed transcriptional state. Although first identified in embryonal stem cells, bivalent genes have now been associated with tumorigenesis and cancer progression. Emerging evidence indicates the implication of bivalent gene regulation in glioma heterogeneity and plasticity, mainly involving Homeobox genes, Wingless-Type MMTV Integration Site Family Members, Hedgehog protein, and Solute Carrier Family members. These genes control a wide variety of cellular functions, including cellular differentiation during early organism development, regulation of cell growth, invasion, migration, angiogenesis, therapy resistance, and apoptosis. In this review, we discuss the implication of bivalent genes in glioma pathogenesis and their potential therapeutic targeting options.

scholarly journals Determination of DNA binding specificities of mutated zinc finger domains

FEBS Letters ◽  
1991 ◽  
Vol 283 (1) ◽  
pp. 23-26 ◽  
Author(s):  
Hans-Jürgen Thiesen ◽  
Christian Bach
Keyword(s):  
Dna Binding ◽  
Zinc Finger ◽  
Zinc Finger Domains

scholarly journals MicroRNA-342 Prohibits Proliferation and Invasion of Melanoma Cells by Directly Targeting Zinc-Finger E-Box-Binding Homeobox 1

2018 ◽  
Vol 26 (9) ◽  
pp. 1447-1455 ◽  
Author(s):  
Quan Shi ◽  
Qi He ◽  
Jing Wei
Keyword(s):  
Cell Proliferation ◽  
Zinc Finger ◽  
Ectopic Expression ◽  
Melanoma Cells ◽  
Potential Candidate ◽  
E Box ◽  
Direct Target Gene ◽  
Direct Target ◽  
Proliferation And Invasion ◽  
Zeb1 Expression

As documented in numerous studies, microRNAs (miRNAs) play key roles in various biological processes associated with melanoma occurrence and development. In this study, we found that miRNA-342 (miR-342) was significantly downregulated in melanoma tissues and cell lines. Additionally, the ectopic expression of miR-342 prohibited the cell proliferation and invasion of melanoma. Moreover, zinc-finger E-box-binding homeobox 1 (ZEB1) was identified as a direct target gene of miR-342 in melanoma. Similar with the results induced by miR-342 overexpression, ZEB1 knockdown attenuated cell proliferation and invasion in melanoma. Furthermore, the restoration of ZEB1 expression reversed the suppressive effects of miR-342 on the proliferation and invasion of melanoma cells. These findings suggest that miR-342 may play tumor-suppressing roles in melanoma, at least partially, by directly inhibiting ZEB1 expression. Therefore, miR-342 may be developed as a potential candidate for the treatment of patients with this aggressive type of cancer.

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