Aberrant induction of LMO2 by the E2A-HLF chimeric transcription factor and its implication in leukemogenesis of B-precursor ALL with t(17;19)

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 962-970 ◽  
Author(s):  
Kinuko Hirose ◽  
Takeshi Inukai ◽  
Jiro Kikuchi ◽  
Yusuke Furukawa ◽  
Tomokatsu Ikawa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Line ◽  
Leucine Zipper ◽  
Apoptotic Cell ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Modality ◽  
Transactivation Domain ◽  
Specific Expression ◽  
Human T Cell ◽  
Primary Sample

Abstract LMO2, a critical transcription regulator of hematopoiesis, is involved in human T-cell leukemia. The binding site of proline and acidic amino acid–rich protein (PAR) transcription factors in the promoter of the LMO2 gene plays a central role in hematopoietic-specific expression. E2A-HLF fusion derived from t(17;19) in B-precursor acute lymphoblastic leukemia (ALL) has the transactivation domain of E2A and the basic region/leucine zipper domain of HLF, which is a PAR transcription factor, raising the possibility that E2A-HLF aberrantly induces LMO2 expression. We here demonstrate that cell lines and a primary sample of t(17;19)-ALL expressed LMO2 at significantly higher levels than other B-precursor ALLs did. Transfection of E2A-HLF into a non-t(17;19) B-precursor ALL cell line induced LMO2 gene expression that was dependent on the DNA-binding and transactivation activities of E2A-HLF. The PAR site in the LMO2 gene promoter was critical for E2A-HLF-induced LMO2 expression. Gene silencing of LMO2 in a t(17;19)-ALL cell line by short hairpin RNA induced apoptotic cell death. These observations indicated that E2A-HLF promotes cell survival of t(17;19)-ALL cells by aberrantly up-regulating LMO2 expression. LMO2 could be a target for a new therapeutic modality for extremely chemo-resistant t(17;19)-ALL.

scholarly journals Molecular cloning of cellular genes encoding retinoblastoma-associated proteins: identification of a gene with properties of the transcription factor E2F.

1992 ◽  
Vol 12 (12) ◽  
pp. 5620-5631 ◽  
Author(s):  
B Shan ◽  
X Zhu ◽  
P L Chen ◽  
T Durfee ◽  
Y Yang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mammalian Cells ◽  
Leucine Zipper ◽  
T Antigen ◽  
Transactivation Domain ◽  
Recognition Sequence ◽  
Cellular Genes ◽  
Genes Encoding ◽  
Associated Proteins ◽  
Transcription Factor E2f

The retinoblastoma protein interacts with a number of cellular proteins to form complexes which are probably crucial for its normal physiological function. To identify these proteins, we isolated nine distinct clones by direct screening of cDNA expression libraries using purified RB protein as a probe. One of these clones, Ap12, is expressed predominantly at the G1-S boundary and in the S phase of the cell cycle. The nucleotide sequence of Ap12 has features characteristic of transcription factors. The C-terminal region binds to unphosphorylated RB in regions similar to those to which T antigen binds and contains a transactivation domain. A region containing a potential leucine zipper flanked by basic residues is able to bind an E2F recognition sequence specifically. Expression of Ap12 in mammalian cells significantly enhances E2F-dependent transcriptional activity. These results suggest that Ap12 encodes a protein with properties known to be characteristic of transcription factor E2F.

scholarly journals Erythroid-cell-specific properties of transcription factor GATA-1 revealed by phenotypic rescue of a gene-targeted cell line.

1997 ◽  
Vol 17 (3) ◽  
pp. 1642-1651 ◽  
Author(s):  
M J Weiss ◽  
C Yu ◽  
S H Orkin
Keyword(s):  
Transcription Factor ◽  
Cell Line ◽  
Zinc Finger ◽  
Es Cells ◽  
Embryonic Stem ◽  
Erythroid Cell ◽  
Transactivation Domain ◽  
Stage Of Development ◽  
Erythroid Maturation

The zinc finger transcription factor GATA-1 is essential for erythropoiesis. In its absence, committed erythroid precursors arrest at the proerythroblast stage of development and undergo apoptosis. To study the function of GATA-1 in an erythroid cell environment, we generated an erythroid cell line from in vitro-differentiated GATA-1- murine embryonic stem (ES) cells. These cells, termed G1E for GATA-1- erythroid, proliferate as immature erythroblasts yet complete differentiation upon restoration of GATA-1 function. We used rescue of terminal erythroid maturation in G1E cells as a stringent cellular assay system in which to evaluate the functional relevance of domains of GATA-1 previously characterized in nonhematopoietic cells. At least two major differences were established between domains required in G1E cells and those required in nonhematopoietic cells. First, an obligatory transactivation domain defined in conventional nonhematopoietic cell transfection assays is dispensable for terminal erythroid maturation. Second, the amino (N) zinc finger, which is nonessential for binding to the vast majority of GATA DNA motifs, is strictly required for GATA-1-mediated erythroid differentiation. Our data lead us to propose a model in which a nuclear cofactor(s) interacting with the N-finger facilitates transcriptional action by GATA-1 in erythroid cells. More generally, our experimental approach highlights critical differences in the action of cell-specific transcription proteins in different cellular environments and the power of cell lines derived from genetically modified ES cells to elucidate gene function.

scholarly journals Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas

2015 ◽  
Vol 112 (25) ◽  
pp. 7773-7778 ◽  
Author(s):  
Hyung-Ok Lee ◽  
Xiao He ◽  
Jayati Mookerjee-Basu ◽  
Dai Zhongping ◽  
Xiang Hua ◽  
...  
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Receptor ◽  
Cell Development ◽  
Thymocyte Development ◽  
Tcr Signaling ◽  
Double Positive ◽  
Human T Cell

The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell–specific ThPOK transgene (ThPOKconst mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOKconst RAG-deficient mice, which promotes development to the CD4+8+ (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self-perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation.

scholarly journals A New Mouse Gene, SRG3, Related to the SWI3 of Saccharomyces cerevisiae, Is Required for Apoptosis Induced by Glucocorticoids in a Thymoma Cell Line

1997 ◽  
Vol 185 (10) ◽  
pp. 1827-1836 ◽  
Author(s):  
Sung H. Jeon ◽  
Myeong G. Kang ◽  
Young H. Kim ◽  
Yong H. Jin ◽  
Changjin Lee ◽  
...  
Keyword(s):  
Cell Line ◽  
Leucine Zipper ◽  
Apoptotic Cell ◽  
T Cell Development ◽  
Rabbit Antiserum ◽  
Cell Extract ◽  
Mouse Gene ◽  
Leucine Zipper Motif ◽  
Induced Apoptosis ◽  
Glutamine Rich Region

We isolated a new mouse gene that is highly expressed in thymocytes, testis, and brain. This gene, SRG3, showed a significant sequence homology to SWI3, a yeast transcriptional activator, and its human homolog BAF155. SRG3 encodes 1,100 amino acids and has 33–47% identity with SWI3 protein over three regions. The SRG3 protein contains an acidic NH2 terminus, a myb-like DNA binding domain, a leucine-zipper motif, and a proline- and glutamine-rich region at its COOH terminus. Rabbit antiserum raised against a COOH-terminal polypeptide of the SRG3 recognized a protein with an apparent molecular mass of 155 kD. The serum also detected a 170-kD protein that seems to be a mouse homologue of human BAF170. Immunoprecipitation of cell extract with the antiserum against the mouse SRG3 also brought down a 195-kD protein that could be recognized by an antiserum raised against human SWI2 protein. The results suggest that the SRG3 protein associates with a mouse SWI2. The SRG3 protein is expressed about three times higher in thymocytes than in peripheral lymphocytes. The expression of anti-sense RNA to SRG3 mRNA in a thymoma cell line, S49.1, reduced the expression level of the SRG3 protein, and decreased the apoptotic cell death induced by glucocorticoids. These results suggest that the SRG3 protein is involved in the glucocorticoid-induced apoptosis in the thymoma cell line. This implicates that the SRG3 may play an important regulatory role during T cell development in thymus.

Disrupted co-ordination of Pax-8 and thyroid transcription factor-1 gene expression in a dedifferentiated rat thyroid tumour cell line derived from FRTL-5

1996 ◽  
Vol 150 (3) ◽  
pp. 377-382 ◽  
Author(s):  
C J H van der Kallen ◽  
D C J Spierings ◽  
J H H Thijssen ◽  
M A Blankenstein ◽  
T W A de Bruin
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Line ◽  
Thyroid Peroxidase ◽  
Wild Type ◽  
Specific Expression ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Rat Thyroid ◽  
Transcription Factor 1

Abstract The mutant rat thyroid cell line FRTL-5/TA, isolated from a non-functional tumour which originated spontaneously from wild-type FRTL-5 cells, shows autonomous TSH-independent growth and loss of the thyroid-specific phenotype, lacking thyroid-specific expression of thyroglobulin (Tg) and thyroid peroxidase (TPO) genes. To investigate the role of the transcription factors Pax-8 and thyroid transcription factor-1 (TTF-1) in rat thyroid tumorigenesis, RNA expression of these two thyroid-specific nuclear factors was measured in FRTL-5/TA tumour cells and compared with the expression in wild-type FRTL-5 cells. TTF-1 gene expression was similar to that in wild-type FRTL-5, and showed a similar down-regulation after stimulation with TSH. The finding suggested normal TTF-1 mRNA and protein expression in both cell lines. By contrast, Pax-8 mRNA transcript signal was markedly reduced in FRTL-5/TA cells, reaching levels as low as 8% of the normal, basal level in FRTL-5 cells. These data indicated that the loss of thyroid-specific expression of Tg and TPO genes in FRTL-5/TA cells was not related to changes in TTF-1 gene expression but rather to reduced Pax-8 gene expression. It was concluded that a disruption of the co-ordinated expression of TTF-1 and Pax-8 is implicated in the loss of thyroid phenotype of FRTL-5/TA cells in terms of reduced Tg and TPO expression. Journal of Endocrinology (1996) 150, 377–382

A Novel BACH2-BCL2L1 Fusion Gene in the Burkitt’s Lymphoma Derived Cell Line BLUE-1

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4146-4146
Author(s):  
Seval Türkmen ◽  
Mathias Riehn ◽  
Stefan Mundlos ◽  
Eckhard Thiel ◽  
Thomas Burmeister
Keyword(s):  
Transcription Factor ◽  
T Cell ◽  
Cell Line ◽  
Leucine Zipper ◽  
Fusion Gene ◽  
Fusion Transcript ◽  
Established Cell Line ◽  
Basic Leucine Zipper ◽  
Bac Clone ◽  
Bcl2 Family

Abstract Abnormalities of the long arm of chromosome 6 are a common feature in various B-cell malignancies. However, in most cases the involved genes have not yet clearly been identified. We have molecularly characterized the recently established cell line BLUE-1 that has been derived from a relapsed sporadic Burkitt lymphoma. This cell lines carries a t(6;20)(q15;q11.2) rearrangement in addition to the typical t(8;14) with MYC-IgH fusion. The involved gene loci on chromosomes 6 and 20 were up to now unknown. To identify the involved gene loci on both chromosomes we applied a sequential BAC clone mapping strategy. BAC RP11-243J16 clone (20q11.21, bp 29,756,679–29,925,538) was found to hybridize with der(6) as well as der(20). BAC RP1-104D1 (6q15, bp 91,001,943–91,064,406) also covered the breakpoint region. Two of the involved genes in this region are the transcription factor BACH2 (basic leucine zipper transcription factor 2) on 6q15 and BCL2L1 (BCL-X) on 20q11, a member of the BCL2 anti-apoptosis gene family. We hypothesized that these two genes could be involved and by testing different primer combinations were able to amplify a BACH2-BCL2 fusion mRNA transcript using RT-PCR. In this fusion transcript the first (non-coding) exon of BACH2 was fused to the second (partially coding) exon of BCL2L1 thus effectively placing the BCL2L1 gene under the control of the BACH2 promotor. Western blot analysis showed a strong expression of BCL2L1. This is the first report of a fusion gene involving the genes BACH2 and BCL2L1. The prototype of the BCL2 family, BCL-2 on 18q21.3 is known to play a crucial role in various lymphomas but a clear role for the closely related BCL2L1 gene in lymphomas has not yet been established. BACH2 is known to be expressed in B-cells at various maturation stages and is believed to be involved in the machinery of class switch recombination (CSR). Bach2 −/− mice show increased IgM but decreased IgG and IgA levels and a deficient T cell-independent and T cell-dependent IgG response associated with defective CSR. In summary, this molecularly characterized translocation provides a new tool for studying recurrent 6q aberrations in lymphomas and for the action of the BCL2L1 antiapoptosis gene.

A PAR domain transcription factor is involved in the expression from a hematopoietic-specific promoter for the human LMO2 gene

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4757-4764 ◽  
Author(s):  
Scott C. Crable ◽  
Kathleen P. Anderson
Keyword(s):  
Transcription Factor ◽  
Protein Interactions ◽  
Leucine Zipper ◽  
Cell Lineage ◽  
Erythroid Cell ◽  
Protein Protein Interactions ◽  
Consensus Binding Site ◽  
Basic Leucine Zipper ◽  
Specific Expression ◽  
Dna Binding Factors

AbstractThe transcription factor LMO2 is believed to exert its effect through the formation of protein-protein interactions with other DNA-binding factors such as GATA-1 and TAL1. Although LMO2 has been shown to be critical for the formation of the erythroid cell lineage, the gene is also expressed in a number of nonerythroid tissues. In this report, we demonstrate that the more distal of the 2 promoters for the LMO2 gene is highly restricted in its pattern of expression, directing the hematopoietic-specific expression of this gene. Deletion and mutation analyses have identified a critical cis element in the first untranslated exon of the gene. This element is a consensus-binding site for a small family of basic leucine zipper proteins containing a proline and acidic amino acid–rich (PAR) domain. Although all 3 members of this family are produced in erythroid cells, only 2 of these proteins, thyrotroph embryonic factor and hepatic leukemia factor, can activate transcription from this LMO2 promoter element. These findings represent a novel mechanism in erythroid gene regulation because PAR proteins have not previously been implicated in this process.

scholarly journals The Minimal Transactivation Domain of the Basic Motif-Leucine Zipper Transcription Factor NRL Interacts with TATA-binding Protein

2004 ◽  
Vol 279 (45) ◽  
pp. 47233-47241 ◽  
Author(s):  
James S. Friedman ◽  
Hemant Khanna ◽  
Prabodh K. Swain ◽  
Raphael DeNicola ◽  
Hong Cheng ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Leucine Zipper ◽  
Binding Protein ◽  
Tata Binding Protein ◽  
Transactivation Domain
Sign in / Sign up

Export Citation Format

Share Document