scholarly journals Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease

2006 ◽  
Vol 203 (11) ◽  
pp. 2529-2540 ◽  
Author(s):  
Melissa Kristine Middleton ◽  
Alicia Marie Zukas ◽  
Tanya Rubinstein ◽  
Michele Jacob ◽  
Peijuan Zhu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Consensus Sequence ◽  
Leukemic Cell ◽  
Myeloproliferative Disorder ◽  
Myelogenous Leukemia ◽  
Nuclear Accumulation ◽  
Myeloproliferative Disease ◽  
Phosphatidylinositol 3 Kinase ◽  
Chronic Stage ◽  
Transplantable Leukemia

Though Abl inhibitors are often successful therapies for the initial stages of chronic myelogenous leukemia (CML), refractory cases highlight the need for novel molecular insights. We demonstrate that mice deficient in the enzyme 12/15-lipoxygenase (12/15-LO) develop a myeloproliferative disorder (MPD) that progresses to transplantable leukemia. Although not associated with dysregulation of Abl, cells isolated from chronic stage 12/15-LO–deficient (Alox15) mice exhibit increased activation of the phosphatidylinositol 3–kinase (PI3-K) pathway, as indicated by enhanced phosphorylation of Akt. Furthermore, the transcription factor interferon consensus sequence binding protein (ICSBP) is hyperphosphorylated and displays decreased nuclear accumulation, translating into increased levels of expression of the oncoprotein Bcl-2. The ICSBP defect, exaggerated levels of Bcl-2, and prolonged leukemic cell survival associated with chronic stage Alox15 MPD are all reversible upon treatment with a PI3-K inhibitor. Remarkably, the evolution of Alox15 MPD to leukemia is associated with additional regulation of ICSBP on an RNA level, highlighting the potential usefulness of the Alox15 model for understanding the transition of CML to crisis. Finally, 12/15-LO expression suppresses the growth of a human CML–derived cell line. These data identify 12/15-LO as an important suppressor of MPD via its role as a critical upstream effector in the regulation of PI3-K–dependent ICSBP phosphorylation.

scholarly journals Expression of Interferon Consensus Sequence Binding Protein (ICSBP) Is Downregulated in Bcr-Abl-Induced Murine Chronic Myelogenous Leukemia-Like Disease, and Forced Coexpression of ICSBP Inhibits Bcr-Abl-Induced Myeloproliferative Disorder

2000 ◽  
Vol 20 (4) ◽  
pp. 1149-1161 ◽  
Author(s):  
Sheryl X. Hao ◽  
Ruibao Ren
Keyword(s):  
Tumor Suppressor ◽  
Chronic Myelogenous Leukemia ◽  
Murine Model ◽  
Binding Protein ◽  
Consensus Sequence ◽  
Chronic Phase ◽  
Myeloproliferative Disorder ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Hematopoietic Stem

ABSTRACT Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder resulting from the neoplastic transformation of a hematopoietic stem cell. The majority of cases of CML are associated with the (9;22) chromosome translocation that generates thebcr-abl chimeric gene. Alpha interferon (IFN-α) treatment induces hematological remission and prolongs life in 75% of CML patients in the chronic phase. It has been shown that mice deficient in interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor family, manifest a CML-like syndrome. We have shown that expression of Bcr-Abl in bone marrow (BM) cells from 5-fluorouracil (5-FU)-treated mice by retroviral transduction efficiently induces a myeloproliferative disease in mice resembling human CML. To directly test whether icsbp can function as a tumor suppressor gene, we examined the effect of ICSBP on Bcr-Abl-induced CML-like disease using this murine model for CML. We found that expression of the ICSBP protein was significantly decreased in Bcr-Abl-induced CML-like disease. Forced coexpression of ICSBP inhibited the Bcr-Abl-induced colony formation of BM cells from 5-FU-treated mice in vitro and Bcr-Abl-induced CML-like disease in vivo. Interestingly, coexpression of ICSBP and Bcr-Abl induced a transient B-lymphoproliferative disorder in the murine model of Bcr-Abl-induced CML-like disease. Overexpression of ICSBP consistently promotes rather than inhibits Bcr-Abl-induced B lymphoproliferation in a murine model where BM cells from non-5-FU-treated donors were used, indicating that ICSBP has a specific antitumor activity toward myeloid neoplasms. We also found that overexpression of ICSBP negatively regulated normal hematopoiesis. These data provide direct evidence that ICSBP can act as a tumor suppressor that regulates normal and neoplastic proliferation of hematopoietic cells.

Differential Binding Activity of the Transcription Factor LIL-Stat in Immature and Differentiated Normal and Leukemic Myeloid Cells

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1364-1373 ◽  
Author(s):  
Leonore M.L. Tuyt ◽  
Krista Bregman ◽  
Chantal Lummen ◽  
Wim H.A. Dokter ◽  
Edo Vellenga
Keyword(s):  
Transcription Factor ◽  
Consensus Sequence ◽  
Leukemic Cell ◽  
Binding Activity ◽  
Band Shift ◽  
Leukemic Cell Lines ◽  
Nuclear Extracts ◽  
Macrophage Colony ◽  
American Society ◽  
Responsive Element

Cytokines and growth factors induce activation of the family of signal transducers and activators of transcription (Stats) that directly activate gene expression. Recently, constitutively activated Stat1, Stat3, and Stat5 were identified in nuclear extracts of acute myeloid leukemia (AML) patients, suggesting involvement of constitutive Stat activity in the events of leukemogenesis. In the present study, blasts of nine AML cases were investigated for the constitutive binding activity of the recently identified transcription factor LIL-Stat (LPS- and IL-1-inducible Stat). Band-shift assays were performed using the LPS-and IL-1-responsive element (LILRE) oligonucleotide, a gamma interferon activation site-like site that is present in the human IL-1β promoter. Constitutive LIL-Stat binding activity was observed in three leukemic cell lines and in seven out of nine AML cases. Transient transfection studies with a reporter plasmid containing three sequential LIL-Stat binding sites showed distinct transcriptional activity of LIL-Stat only in those AML blasts that constitutively expressed LIL-Stat. In CD34+ cells LIL-Stat also constitutively bound to its consensus sequence. However, when these cells were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and stem cell factor (SCF) for differentiation along the monocytic lineage, the LIL-Stat binding activity disappeared totally. In agreement with these findings neither mature monocytes nor granulocytes showed constitutive or inducible LIL-Stat binding activity. We conclude that the LIL-Stat transcription factor is constitutively activated in undifferentiated and leukemic hematopoietic cells, but not in mature cells. This may suggest a role for this transcription factor in the process of differentiation. © 1998 by The American Society of Hematology.

Chronic Leukemia of Childhood

1984 ◽  
Vol 6 (1) ◽  
pp. 26-30
Author(s):  
Steven J. Weisman ◽  
Roger L. Berkow ◽  
Robert L. Baehner
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Fatal Outcome ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myeloproliferative Disorder ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Myeloproliferative Disease ◽  
Blastic Crisis ◽  
Hemoglobin F

The chronic leukemias of childhood include chronic myelogenous leukemia (CML) and chronic lymphocytic leukemia. Chronic lymphocytic leukemia in childhood is a monoclonal B-cell neoplasm of great infrequency. CML occurs with enough frequency to warrant a review for the general pediatrician. CML is a clonal (derived from a single cell line) myeloproliferative disorder that has two major forms in childhood, which, as a group, account for 2% to 5% of the childhood leukemias. "Adult" CML is a classic clonal myeloproliferative disease demonstrating the Philadelphia chromosome (Ph1). Its chronic phase lasts 2 to 3 years, then evolves into an acute phase which terminates in the blastic crisis. "Juvenile" CML is more often seen in infants and toddlers and is notable for the presence of rash, adenopathy, absence of the Ph1 chromosome, and elevated level of hemoglobin F. In fact, the two diseases have less in common than the similar names would imply. Approximately one third of CML in childhood is of the juvenile type. A third type of myeloproliferative disorder resembling CML has been reported in two pairs of infant siblings. It clinically resembles juvenile CML, but does not appear to have the nearly universally fatal outcome. Finally, a familial myeloproliferative syndrome, which most closely resembles adult CML, has been reported in a large kindred.

Differential Binding Activity of the Transcription Factor LIL-Stat in Immature and Differentiated Normal and Leukemic Myeloid Cells

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1364-1373 ◽  
Author(s):  
Leonore M.L. Tuyt ◽  
Krista Bregman ◽  
Chantal Lummen ◽  
Wim H.A. Dokter ◽  
Edo Vellenga
Keyword(s):  
Transcription Factor ◽  
Consensus Sequence ◽  
Leukemic Cell ◽  
Binding Activity ◽  
Band Shift ◽  
Leukemic Cell Lines ◽  
Nuclear Extracts ◽  
Macrophage Colony ◽  
American Society ◽  
Responsive Element

Abstract Cytokines and growth factors induce activation of the family of signal transducers and activators of transcription (Stats) that directly activate gene expression. Recently, constitutively activated Stat1, Stat3, and Stat5 were identified in nuclear extracts of acute myeloid leukemia (AML) patients, suggesting involvement of constitutive Stat activity in the events of leukemogenesis. In the present study, blasts of nine AML cases were investigated for the constitutive binding activity of the recently identified transcription factor LIL-Stat (LPS- and IL-1-inducible Stat). Band-shift assays were performed using the LPS-and IL-1-responsive element (LILRE) oligonucleotide, a gamma interferon activation site-like site that is present in the human IL-1β promoter. Constitutive LIL-Stat binding activity was observed in three leukemic cell lines and in seven out of nine AML cases. Transient transfection studies with a reporter plasmid containing three sequential LIL-Stat binding sites showed distinct transcriptional activity of LIL-Stat only in those AML blasts that constitutively expressed LIL-Stat. In CD34+ cells LIL-Stat also constitutively bound to its consensus sequence. However, when these cells were cultured in the presence of macrophage-colony stimulating factor (M-CSF) and stem cell factor (SCF) for differentiation along the monocytic lineage, the LIL-Stat binding activity disappeared totally. In agreement with these findings neither mature monocytes nor granulocytes showed constitutive or inducible LIL-Stat binding activity. We conclude that the LIL-Stat transcription factor is constitutively activated in undifferentiated and leukemic hematopoietic cells, but not in mature cells. This may suggest a role for this transcription factor in the process of differentiation. © 1998 by The American Society of Hematology.

scholarly journals ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3813-3820 ◽  
Author(s):  
Valentina Nardi ◽  
Olaia Naveiras ◽  
Mohammad Azam ◽  
George Q. Daley
Keyword(s):  
Murine Model ◽  
Consensus Sequence ◽  
Myelogenous Leukemia ◽  
Transformed Cells ◽  
Type I ◽  
Immune Protection ◽  
Immune Mechanism ◽  
Type I Ifns ◽  
New Strategies

Abstract Interferon (IFN) is effective at inducing complete remissions in patients with chronic myelogenous leukemia (CML), and evidence supports an immune mechanism. Here we show that the type I IFNs (alpha and beta) regulate expression of the IFN consensus sequence-binding protein (ICSBP) in BCR-ABL–transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of BCR-ABL–induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the type I IFNs and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the antileukemic response of IFNs suggest new strategies for immunotherapy of CML.

Transcription factor 3 controls cell proliferation and migration in glioblastoma multiforme cell lines

2016 ◽  
Vol 94 (3) ◽  
pp. 247-255 ◽  
Author(s):  
Ruiting Li ◽  
Yinghui Li ◽  
Xin Hu ◽  
Haiwei Lian ◽  
Lei Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glioblastoma Multiforme ◽  
Cell Lines ◽  
Normal Brain ◽  
Phosphatidylinositol 3 Kinase ◽  
T Cell Factor ◽  
And Migration ◽  
Induced Apoptosis ◽  
Proliferation And Migration ◽  
Transcription Factor 3

Transcription factor 3 (TCF3) is a member of the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor family. Recent studies have demonstrated its potential carcinogenic properties. Here we show that TCF3 was upregulated in glioma tissues compared with normal brain tissues. This upregulation of the TCF3 gene probably has functional significance in brain-tumor progression. Our studies on glioblastoma multiforme (GBM) cell lines show that knock-down of TCF3 induced apoptosis and inhibited cell migration. Further analysis revealed that down-regulation of TCF3 gene expression inhibits Akt and Erk1/2 activation, suggesting that the carcinogenic properties of TCF3 in GBM are partially mediated by the phosphatidylinositol 3-kinase–Akt and MAPK–Erk signaling pathways. Considered together, the results of this study demonstrate that high levels of TCF3 in gliomas potentially promote glioma development through the Akt and Erk pathways.

scholarly journals Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 1938-1947 ◽  
Author(s):  
Tomohiko Tamura ◽  
Pratima Thotakura ◽  
Tetsuya S. Tanaka ◽  
Minoru S. H. Ko ◽  
Keiko Ozato
Keyword(s):  
Transcription Factor ◽  
Cystatin C ◽  
Target Genes ◽  
De Novo ◽  
Consensus Sequence ◽  
Binding Motif ◽  
Microarray Gene Expression ◽  
Cathepsin C ◽  
Cis Element

Abstract Interferon regulatory factor-8 (IRF-8)/interferon consensus sequence–binding protein (ICSBP) is a transcription factor that controls myeloid-cell development. Microarray gene expression analysis of Irf-8-/- myeloid progenitor cells expressing an IRF-8/estrogen receptor chimera (which differentiate into macrophages after addition of estradiol) was used to identify 69 genes altered by IRF-8 during early differentiation (62 up-regulated and 7 down-regulated). Among them, 4 lysosomal/endosomal enzyme-related genes (cystatin C, cathepsin C, lysozyme, and prosaposin) did not require de novo protein synthesis for induction, suggesting that they were direct targets of IRF-8. We developed a reporter assay system employing a self-inactivating retrovirus and analyzed the cystatin C and cathepsin C promoters. We found that a unique cis element mediates IRF-8–induced activation of both promoters. Similar elements were also found in other IRF-8 target genes with a consensus sequence (GAAANN[N]GGAA) comprising a core IRF-binding motif and an Ets-binding motif; this sequence is similar but distinct from the previously reported Ets/IRF composite element. Chromatin immunoprecipitation assays demonstrated that IRF-8 and the PU.1 Ets transcription factor bind to this element in vivo. Collectively, these data indicate that IRF-8 stimulates transcription of target genes through a novel cis element to specify macrophage differentiation.

Abstract MP12: The Mef2c Transcription Factor Regulates The Renin Cell Identity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Omar E Guessoum ◽  
Kristyna Kupkova ◽  
Nathan Sheffield ◽  
Maria Luisa Sequeira Lopez ◽  
Roberto A Gomez
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Consensus Sequence ◽  
Renin Angiotensin System ◽  
Fold Increase ◽  
Conditional Knockout ◽  
Motif Analysis ◽  
Regulation Of Expression ◽  
Cell Identity

Introduction: The Renin-Angiotensin-System is essential to maintain blood pressure and fluid electrolyte homeostasis. Because precise regulation of expression and release of renin is critical for survival, understanding the molecular regulation of the renin cell identity is a vital area of study. Advances in epigenetics have enabled finer dissection of chromatin factors which maintain the identity of the renin cell. By studying genes with heightened accessibility profiles that are unique to the JG cell, we now have the capacity to unravel the determinants of the renin cell identity. Hypothesis: That transcription factors central to the governance of renin cell identity can be identified through the Assay for Transposase Accessible Chromatin (ATAC-seq) differential accessibility analysis. Methods: Native renin cell ATAC-seq was compared to existing ENCODE ATAC-seq datasets from 40 other cell types to define regions/peaks which characterize the JG program. Peaks with high intensity and ≥2-fold increase in signal were selected for Motif analysis to search for transcription factors (TFs) whose consensus sequence is enriched in those regions. Identified TFs were then selected for validation by in-situ hybridization and conditional deletion in renin cells. Results: 1) The Mef2c transcription factor was identified as having a consensus sequence in regulatory regions unique to the JG cell. It has clear expression in RNA-seq of renin cells (65 transcripts per million, n=3) and a predicted binding site in the renin gene. These results were validated by in-situ hybridization where signal localized at the JG area was detected in concordance with our in-silico results. 2) We generated Mef2c conditional knockout animals using our Ren1d-Cre mouse to study the effect in renin expression and identity. These mice displayed reduced renin immunostaining at the JG area and a 40% reduction in renin mRNA expression by qPCR from kidney cortices relative to wild-type (n=2, preliminary data). Conclusions: Our studies identified Mef2c as a TF target which likely has an essential role in maintaining and preserving renin cell identity. Experiments involving transcriptomics and epigenomics are ongoing to understand the changes wrought by Mef2c deletion in renin cells.

scholarly journals Adaptive evolution of transcription factor binding affinities

2017 ◽  
Author(s):  
Jungeui Hong ◽  
Nathan Brandt ◽  
Ally Yang ◽  
Tim Hughes ◽  
David Gresham
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Adaptive Evolution ◽  
Consensus Sequence ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Missense Mutations ◽  
Binding Affinities ◽  
Synonymous Mutations

Understanding the molecular basis of gene expression evolution is a central problem in evolutionary biology. However, connecting changes in gene expression to increased fitness, and identifying the functional basis of those changes, remains challenging. To study adaptive evolution of gene expression in real time, we performed long term experimental evolution (LTEE) of Saccharomyces cerevisiae (budding yeast) in ammonium-limited chemostats. Following several hundred generations of continuous selection we found significant divergence of nitrogen-responsive gene expression in lineages with increased fitness. In multiple independent lineages we found repeated selection for non-synonymous mutations in the zinc finger DNA binding domain of the activating transcription factor (TF), GAT1, that operates within incoherent feedforward loops to control expression of the nitrogen catabolite repression (NCR) regulon. Missense mutations in the DNA binding domain of GAT1 reduce its binding affinity for the GATAA consensus sequence in a promoter-specific manner, resulting in increased expression of ammonium permease genes via both direct and indirect effects, thereby conferring increased fitness. We find that altered transcriptional output of the NCR regulon results in antagonistic pleiotropy in alternate environments and that the DNA binding domain of GAT1 is subject to purifying selection in natural populations. Our study shows that adaptive evolution of gene expression can entail tuning expression output by quantitative changes in TF binding affinities while maintaining the overall topology of a gene regulatory network.

scholarly journals Clinical characteristics and prognosis of 50 patients with a myeloproliferative syndrome and deletion of part of the long arm of chromosome 5

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 189-197 ◽  
Author(s):  
GW Dewald ◽  
MP Davis ◽  
RV Pierre ◽  
JR O'Fallon ◽  
HC Hoagland
Keyword(s):  
Cox Model ◽  
Myeloproliferative Disorder ◽  
Refractory Anemia ◽  
Myeloproliferative Disease ◽  
Poor Survival ◽  
Prior Chemotherapy ◽  
Myeloproliferative Syndrome ◽  
Additional Chromosome ◽  
Group 2 ◽  
Group 1

Of 50 consecutive patients (30 female and 20 male; median age,70 years) with a myeloproliferative disorder and a 5q- chromosome, 12 (24%) had refractory anemia, 16 (32%) had refractory anemia with excess blasts, 13 (26%) had acute nonlymphocytic leukemia, six (12%) had the 5q- syndrome, and three (6%) had an unclassifiable myeloproliferative disease. Twenty-five patients had only a 5q- anomaly (group 1), and 25 had a 5q- plus additional chromosome abnormalities (group 2). Four types of 5q- anomalies were recognized: a del(5)(q13q33) occurred in 39 patients, a del(5)(q31q35) in nine, a del(5)(q22q33) in one, and a del(5)(q13q35) in one. The survival distribution for patients in group 1 was significantly better (P = .012) than for those in group 2. Cox- model analyses indicated that having a 5q- chromosome and other abnormalities is significantly (P less than .01) associated with poor survival even after adjustment for the effects of other important factors such as type of disease, age, and sex. The two groups had similar distributions of most variables, including age, sex, and disease types. However, patients in group 1 had a significantly higher platelet count and mean corpuscular volume than those in group 2. Only two patients in group 1 had had prior chemotherapy, but nine in group 2 had had either prior chemotherapy or radiation or both, and one patient in group 2 had had heavy exposure to pesticides.

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