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LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding.
Layer JH, Alford CE, McDonald WH, Davé UP
(2016) Mol Cell Biol 36: 488-506
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Amino Acid Substitution, Cell Line, DNA-Binding Proteins, Humans, Jurkat Cells, LIM Domain Proteins, Leukemia, T-Cell, Molecular Sequence Data, Mutation, Protein Interaction Domains and Motifs, Protein Interaction Maps, Protein Stability, Proto-Oncogene Proteins, Transcription Factors, Transcriptional Activation
Show Abstract · Added January 26, 2016
LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R(320)LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild-type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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2 Members
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17 MeSH Terms
Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias.
Goodings C, Tripathi R, Cleveland SM, Elliott N, Guo Y, Shyr Y, Davé UP
(2015) Leuk Res 39: 100-9
MeSH Terms: Adaptor Proteins, Signal Transducing, Basic Helix-Loop-Helix Transcription Factors, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Transformation, Neoplastic, Humans, LIM Domain Proteins, Leukemia, T-Cell, Protein Multimerization, Proto-Oncogene Proteins, Response Elements, Transcription Factor 3
Show Abstract · Added February 19, 2015
LIM domain only-2 (LMO2) overexpression in T cells induces leukemia but the molecular mechanism remains to be elucidated. In hematopoietic stem and progenitor cells, Lmo2 is part of a protein complex comprised of class II basic helix loop helix proteins, Tal1and Lyl1. The latter transcription factors heterodimerize with E2A proteins like E47 and Heb to bind E boxes. LMO2 and TAL1 or LYL1 cooperate to induce T-ALL in mouse models, and are concordantly expressed in human T-ALL. Furthermore, LMO2 cooperates with the loss of E2A suggesting that LMO2 functions by creating a deficiency of E2A. In this study, we tested this hypothesis in Lmo2-induced T-ALL cell lines. We transduced these lines with an E47/estrogen receptor fusion construct that could be forced to homodimerize with 4-hydroxytamoxifen. We discovered that forced homodimerization induced growth arrest in 2 of the 4 lines tested. The lines sensitive to E47 homodimerization accumulated in G1 and had reduced S phase entry. We analyzed the transcriptome of a resistant and a sensitive line to discern the E47 targets responsible for the cellular effects. Our results suggest that E47 has diverse effects in T-ALL but that functional deficiency of E47 is not a universal feature of Lmo2-induced T-ALL.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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12 MeSH Terms
The microfluidic multitrap nanophysiometer for hematologic cancer cell characterization reveals temporal sensitivity of the calcein-AM efflux assay.
Byrd TF, Hoang LT, Kim EG, Pfister ME, Werner EM, Arndt SE, Chamberlain JW, Hughey JJ, Nguyen BA, Schneibel EJ, Wertz LL, Whitfield JS, Wikswo JP, Seale KT
(2014) Sci Rep 4: 5117
MeSH Terms: Animals, Calcium-Binding Proteins, Cell Separation, Equipment Design, Equipment Failure Analysis, Flow Cytometry, Fluoresceins, Humans, Jurkat Cells, Leukemia, T-Cell, Microfluidic Analytical Techniques, Nanotechnology, Optical Tweezers, Reproducibility of Results, Sensitivity and Specificity, Tissue Array Analysis
Show Abstract · Added February 2, 2015
Cytometric studies utilizing flow cytometry or multi-well culture plate fluorometry are often limited by a deficit in temporal resolution and a lack of single cell consideration. Unfortunately, many cellular processes, including signaling, motility, and molecular transport, occur transiently over relatively short periods of time and at different magnitudes between cells. Here we demonstrate the multitrap nanophysiometer (MTNP), a low-volume microfluidic platform housing an array of cell traps, as an effective tool that can be used to study individual unattached cells over time with precise control over the intercellular microenvironment. We show how the MTNP platform can be used for hematologic cancer cell characterization by measuring single T cell levels of CRAC channel modulation, non-translational motility, and ABC-transporter inhibition via a calcein-AM efflux assay. The transporter data indicate that Jurkat T cells exposed to indomethacin continue to accumulate fluorescent calcein for over 60 minutes after calcein-AM is removed from the extracellular space.
1 Communities
2 Members
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16 MeSH Terms
LMO2 induces T-cell leukemia with epigenetic deregulation of CD4.
Cleveland SM, Goodings C, Tripathi RM, Elliott N, Thompson MA, Guo Y, Shyr Y, Davé UP
(2014) Exp Hematol 42: 581-93.e5
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, CD4 Antigens, Epigenesis, Genetic, Humans, In Situ Hybridization, Fluorescence, LIM Domain Proteins, Leukemia, T-Cell, Mice, Mice, Transgenic, Proto-Oncogene Proteins
Show Abstract · Added June 26, 2014
In this study, we present a remarkable clonal cell line, 32080, derived from a CD2-Lmo2- transgenic T-cell leukemia with differentiation arrest at the transition from the intermediate single positive to double positive stages of T-cell development. We observed that 32080 cells had a striking variegated pattern in CD4 expression. There was cell-to-cell variability, with some cells expressing no CD4 and others expressing high CD4. The two populations were isogenic and yet differed in their rates of apoptosis and sensitivity to glucocorticoid. We sorted the 32080 line for CD4-positive or CD4-negative cells and observed them in culture. After 1 week, both sorted populations showed variegated CD4 expression, like the parental line, showing that the two populations could interconvert. We determined that cell replication was necessary to transit from CD4(+) to CD4(-) and CD4(-) to CD4(+). Lmo2 knockdown decreased CD4 expression, while inhibition of intracellular NOTCH1 or histone deacetylase activity induced CD4 expression. Enforced expression of RUNX1 repressed CD4 expression. We analyzed the CD4 locus by Histone 3 chromatin immunoprecipitation and found silencing marks in the CD4(-) cells and activating marks in the CD4(+) population. The 32080 cell line is a striking model of intermediate single positive to double positive T-cell plasticity and invokes a novel mechanism for LMO2's oncogenic functions.
Copyright © 2014 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
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11 MeSH Terms
LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways.
Smith S, Tripathi R, Goodings C, Cleveland S, Mathias E, Hardaway JA, Elliott N, Yi Y, Chen X, Downing J, Mullighan C, Swing DA, Tessarollo L, Li L, Love P, Jenkins NA, Copeland NG, Thompson MA, Du Y, Davé UP
(2014) PLoS One 9: e85883
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, CD2 Antigens, Carcinogenesis, Cell Line, Tumor, E-Box Elements, Gene Expression Regulation, Leukemic, Homeodomain Proteins, Humans, LIM Domain Proteins, Leukemia, T-Cell, Mice, Mice, Transgenic, Molecular Sequence Data, Neoplasm Proteins, Oncogenes, Penetrance, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Signal Transduction, Transcription Factors, Transcription, Genetic, Up-Regulation
Show Abstract · Added March 5, 2014
The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP-ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2-Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype.
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27 MeSH Terms
The loss of the BH3-only Bcl-2 family member Bid delays T-cell leukemogenesis in Atm-/- mice.
Biswas S, Shi Q, Wernick A, Aiello A, Zinkel SS
(2013) Cell Death Differ 20: 869-77
MeSH Terms: Animals, Annexin A5, Apoptosis, Ataxia Telangiectasia Mutated Proteins, BH3 Interacting Domain Death Agonist Protein, Cell Cycle Proteins, Checkpoint Kinase 1, Chromosomal Proteins, Non-Histone, DNA Damage, DNA-Binding Proteins, Disease Models, Animal, Female, Leukemia, T-Cell, Male, Mice, Mice, Knockout, Protein Kinases, Protein-Serine-Threonine Kinases, T-Lymphocytes, Thymocytes, Tumor Suppressor Proteins, Tumor Suppressor p53-Binding Protein 1
Show Abstract · Added August 22, 2013
Multicellular organisms maintain genomic integrity and resist tumorigenesis through a tightly regulated DNA damage response (DDR) that prevents propagation of deleterious mutations either through DNA repair or programmed cell death. An impaired DDR leads to tumorigenesis that is accelerated when programmed cell death is prevented. Loss of the ATM (ataxia telangiectasia mutated)-mediated DDR in mice results in T-cell leukemia driven by accumulation of DNA damage accrued during normal T-cell development. Pro-apoptotic BH3-only Bid is a substrate of Atm, and Bid phosphorylation is required for proper cell cycle checkpoint control and regulation of hematopoietic function. In this report, we demonstrate that, surprisingly, loss of Bid increases the latency of leukemogenesis in Atm-/- mice. Bid-/-Atm-/- mice display impaired checkpoint control and increased cell death of DN3 thymocytes. Loss of Bid thus inhibits T-cell tumorigenesis by increasing clearance of damaged cells, and preventing propagation of deleterious mutations.
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22 MeSH Terms
Lmo2 induces hematopoietic stem cell-like features in T-cell progenitor cells prior to leukemia.
Cleveland SM, Smith S, Tripathi R, Mathias EM, Goodings C, Elliott N, Peng D, El-Rifai W, Yi D, Chen X, Li L, Mullighan C, Downing JR, Love P, Davé UP
(2013) Stem Cells 31: 882-94
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Cell Differentiation, Cell Lineage, Gene Expression, Hematopoietic Stem Cells, LIM Domain Proteins, Leukemia, T-Cell, Mice, Mice, Inbred C57BL, Mice, Transgenic, Precursor Cells, T-Lymphoid
Show Abstract · Added September 3, 2013
LIM domain only 2 (Lmo2) is frequently deregulated in sporadic and gene therapy-induced acute T-cell lymphoblastic leukemia (T-ALL) where its overexpression is an important initiating mutational event. In transgenic and retroviral mouse models, Lmo2 expression can be enforced in multiple hematopoietic lineages but leukemia only arises from T cells. These data suggest that Lmo2 confers clonal growth advantage in T-cell progenitors. We analyzed proliferation, differentiation, and cell death in CD2-Lmo2 transgenic thymic progenitor cells to understand the cellular effects of enforced Lmo2 expression. Most impressively, Lmo2 transgenic T-cell progenitor cells were blocked in differentiation, quiescent, and immortalized in vitro on OP9-DL1 stromal cells. These cellular effects were concordant with a transcriptional signature in Lmo2 transgenic T-cell progenitor cells that is also present in hematopoietic stem cells (HSCs) and early T-cell precursor ALL. These results are significant in light of the crucial role of Lmo2 in the maintenance of the HSC. The cellular effects and transcriptional effects have implications for LMO2-dependent leukemogenesis and the treatment of LMO2-induced T-ALL.
Copyright © 2013 AlphaMed Press.
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4 Members
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12 MeSH Terms
Gene therapy insertional mutagenesis insights.
Davé UP, Jenkins NA, Copeland NG
(2004) Science 303: 333
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, DNA-Binding Proteins, Gene Expression, Genetic Therapy, Genetic Vectors, Humans, LIM Domain Proteins, Leukemia, T-Cell, Metalloproteins, Mice, Mutagenesis, Insertional, Proto-Oncogene Proteins, Receptors, Interleukin-2, Retroviridae, Severe Combined Immunodeficiency, Virus Integration
Added March 5, 2014
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1 Members
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17 MeSH Terms
Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia.
Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, Wen W, Kersey JH, Robison LL
(2000) Br J Cancer 82: 234-40
MeSH Terms: Adolescent, Birth Intervals, Case-Control Studies, Child, Child Day Care Centers, Child, Preschool, Demography, Family Characteristics, Female, Humans, Immunophenotyping, Infant, Infant, Newborn, Infections, Leukemia, B-Cell, Leukemia, T-Cell, Male, Odds Ratio, Precursor Cell Lymphoblastic Leukemia-Lymphoma
Show Abstract · Added December 10, 2013
To investigate if decreased exposure to common childhood infections is associated with risk of childhood acute lymphoblastic leukaemia (ALL) we conducted a case-control study of 1842 newly diagnosed and immunophenotypically defined cases of ALL under age 15, and 1986 matched controls in the US. Data regarding day care, sibship size and common childhood infections were obtained through parental interviews. Data were analysed stratified by leukaemia lineage and separately for 'common' childhood ALL (age 2-5 years, CD19, CD10-positive). Neither attendance at day care nor time at day care was associated with risk of ALL overall or 'common' ALL. Ear infections during infancy were less common among cases, with odds ratios of 0.86, 0.83, 0.71 and 0.69 for 1, 2-4, 5+ episodes, and continuous infections respectively (trend P = 0.026). No effect of sibship size or birth interval was seen. With one exception (ear infections), these data do not support the hypothesis that a decrease in the occurrence of common childhood infection increases risk of ALL.
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19 MeSH Terms
Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies.
Packham G, White EL, Eischen CM, Yang H, Parganas E, Ihle JN, Grillot DA, Zambetti GP, Nuñez G, Cleveland JL
(1998) Genes Dev 12: 2475-87
MeSH Terms: Animals, Apoptosis, Base Sequence, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Hematopoietic Cell Growth Factors, Janus Kinase 2, Leukemia, Myeloid, Leukemia, T-Cell, Mice, Molecular Sequence Data, Mutagenesis, Insertional, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Retroviridae, Sequence Alignment, Tumor Cells, Cultured, bcl-X Protein
Show Abstract · Added March 5, 2014
Bcl-2 family proteins are key regulators of apoptosis and function as cell death antagonists (e.g., Bcl-2, Bcl-XL, and Mcl-1) or agonists (e.g., Bax, Bad, and Bak). Here we report that among the Bcl-2 family of proteins tested (Bcl-2, Bcl-XL, Mcl-1, Bax, Bad, and Bak), Bcl-XL was unique in that its protein levels were tightly regulated by hemopoietins in both immortal and primary myeloid progenitors. Investigating signaling pathways utilized by cytokine receptors established that the regulation of Bcl-XL protein levels is mediated by the Jak kinase pathway and is independent of other signaling effectors including STATs, PI-3' kinase, and Ras. Moreover, we provide the first direct evidence that Bcl-X is altered in cancer, because bcl-X expression was activated selectively by retroviral insertions in murine myeloid and T-cell hemopoietic malignancies. Tumors harboring bcl-X insertions had altered bcl-X RNAs, expressed elevated levels of Bcl-XL protein, and lacked the requirements for cytokines normally essential for cell survival. Finally, overexpression of Bcl-XL effectively protected IL-3-dependent myeloid cells from apoptosis following removal of trophic factors. Therefore, Bcl-XL functions as a key cytokine regulated anti-apoptotic protein in myelopoiesis and contributes to leukemia cell survival.
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19 MeSH Terms