DOCSLIB.ORG

The Effect of Chromosomal Translocations in Acute Leukemias: the LMO2 Paradigm in Transcription and Development I

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Effect of Chromosomal Translocations in Acute Leukemias: the LMO2 Paradigm in Transcription and Development I [CANCER RESEARCH (SUPPL.) 59, 1794s-1798s, April 1, 1999] The Effect of Chromosomal Translocations in Acute Leukemias: The LMO2 Paradigm in Transcription and Development I Terence H. Rabbitts, 2 Katharina Bucher, Grace Chung, Gerald Grutz, Alan Warren, and Yoshi Yamada Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, CB2 2QH United Kingdom Abstract proto-oncogene from a Burkitt's lymphoma translocation breakpoint t(8;14)(q24;q32) revealed that, while the translocated gene was intact, Two general features have emerged about genes that are activated after there were many mutations in both the noncoding first exon and chromosomal translocations in acute forms of cancer. The protein prod- within the coding region itself (4-11). In T-cell acute leukemias, there ucts of these genes are transcription regulators and are involved in are several different chromosomal translocations found in individual developmental processes, and it seems that the subversion of these normal functions accounts for their role in tumorigenesis. The features of the tumors, and the analysis of these has led to the discovery of many LMO family of genes, which encode LIM-domain proteins involved in different, novel genes that can contribute to T-cell tumorigenesis (1). T-cell acute leukemia through chromosomal translocations, typify these These and many other studies have led to two conclusions: abnormal functions in tumorigenesis. For example, the LMO2 protein is (a) many of the chromosomal translocation-activated oncogenes are involved in the formation of multimeric DNA-binding complexes, which transcription regulators in their normal sites of expression, and it is may vary in composition at different stages of hematopoiesis and function this property that is instrumental in their involvement in tumor etiol- to control differentiation of specific lineages. In T cells, enforced expres- ogy after the chromosomal translocation. This was suggested previ- sion of Lmo2 causes aberrant protein complex formation that primarily ously from the early studies on hematopoietic tumor translocations seems to hinder the T-ceU differentiation program. These observations and later, in addition, from the very large range of changes found in underscore the conclusion that protein-protein interaction (in this case, hematopoietic and mesenchymal tumors (reviewed in Ref. 1); and through the LIM domain) is a key determinant in tumorigenesis. Further- (b) the biological role of many chromosomal translocation-acti- more, the study of chromosomal translocations as naturally occurring mutations has been informative about mechanisms in hematopoiesis as vated genes is normally in developmental processes leading to the well as in tumor etiology. notion that subversion of development may be their crucial biological role in tumorigenesis, perhaps explaining why so few of the chromo- Introduction somal translocation-activated genes were previously identified as on- cogenes from other experimental approaches. The LMO 1 and LMO2 The cytogenetic analysis of tumors, particularly those of hemato- LIM-only proteins are involved in T-cell leukemia because of their poietic origin, have revealed that reciprocal chromosomal transloca- ability to interact with other transcription factors. This enhances the tions are recurring features of these tumors (reviewed in Ref. (1). conclusion that protein-protein interaction is a common component of Furthermore, it has become clear that particular chromosomal trans- oncogene function. locations are consistently found in specific tumor subtypes. Through the cloning of the chromosomal breakpoints and identification of Results and Discussion oncogenes at many different breakpoints, followed by transgenic (2) and homologous recombination knock-in analysis (3), it has become The LMO Family Genes. The LMO family of genes was uncov- clear that these abnormal tumor-associated chromosomes are impor- ered (Fig. 1) by the association of LM01 (previously called RBTN1 or tant in the etiology of tumors. The scientific challenge of the last TTG1) with the chromosomal translocation t(11;14)(p15;ql 1). The decade has been to define the contribution of the genes activated by transcription unit was first observed in a T-cell line (12), and the translocations to the course of tumor development and to ascertain mRNA sequence was obtained from its cDNA sequence (13, 14) and whether any general principles can be discerned about these "trans- shown to encode a protein essentially consisting of two zinc-binding location" genes. LIM domains (15). Using an LMO1 probe, the two related genes There are a variety of chromosomal translocations in leukemias and LM02 and LM03 were isolated (previously called RBTN2 or TTG2 in solid tumors of mesenchymal origin (sarcomas), and two main and RBTN3, respectively; Refs. (16, and 17), of which LM02 was outcomes are apparent (1). One of these is confined to lymphoid found located at the junction of the chromosomal translocation t(11; tumors in which the process of antigen receptor rearrangement (im- 14)(p13;ql 1) in T-ALL 3 (16, 18). The LMO-associated chromosomal munoglobulin and T-cell receptor) occurs and which occasionally translocations seem to have occurred by an error of the usual RAG- aberrantly mediates chromosomal translocation. This type of chromo- mediated variable diversity joining recombinase process inasmuch as somal translocation causes oncogene activation resulting from the sequence analysis of the breakpoints on chromosome 1 lp13 detected new chromosomal environment of the rearranged gene, and, in gen- recombinase signal sequences at the junctions and because the joins eral, this means inappropriate gene expression. In this first category of on chromosome 14 in the TCR~ locus or on chromosome 7 in the chromosomal translocation, the B- and T-cell tumors exemplify many TCR~ locus occur precisely at the end of D-segments (19). consistently occurring features. For instance, the cloning of the CMYC The unique feature of the LMO-derived protein sequences is that they are small proteins comprising two tandem LIM domains. These Received 11/11/98; accepted 2/4/99. zinc-binding finger-like structures have structural similarities to the 1 Presented at the "General Motors Cancer Research Foundation Twentieth Annual DNA-binding GATA fingers (20, 21) but as yet no case of a specific Scientific Conference: Developmental Biology and Cancer," June 9-10, 1998, Bethesda, LIM-DNA interaction has been reported; rather the function of this MD. This work was supported by the Medical Research Council and by Grants from the Leukaemia Research Fund (United Kingdom) and the National Foundation for Cancer domain seems to be restricted to protein-protein interaction (see Research (United States). K.B. is supported by the Roche Foundation; G.G. was "LMO2 Functions by Protein Interaction"). supported by an EMBO Fellowship, and Y. Y. by Kyoto University. 2 To whom requests for reprints should be addressed, at MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Hills Road, Cambridge, CB2 3 The abbreviations used are: T-ALL, T-cell acute lymphocytic leukemia; bHLH, 2QH United Kingdom. basic-helix-loop-helix; DN, double negative; Tall, Tall/Scl. 1794s Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 1999 American Association for Cancer Research. LMO GENES IN LEUKEMIA LMO2 Is a Regulator of Mouse Hematopoiesis. To gain insights into the function of the LMO genes in tumorigenesis, an integrated approach has been adopted to attempt to understand the normal Pluri-potent cell Myeloid function at the biological level as well as the function of LMO proteins and to use this information to explore the function in tumors. Mes od~erm-'~~ lineage As a first step, gene targeting was used to introduce null mutations in Lymphoid mouse Lmo2 gene, which showed that Lmo2 is necessary for yolk sac Self-renewa/j lineage erythropoiesis in mouse embryogenesis (22). Furthermore, the use of embryonic stem cells with null mutations of both alleles of Lmo2 in Lmo2 null defect chimeric mice has shown that adult hematopoiesis, including lympho- poiesis and myelopoiesis, fails completely in the absence of Lmo2 Fig. 2. Lmo2 is necessary for adult hematopoiesis in mice. The tissue contribution of embryonic stem cells with homozygous null mutation of Lmo2 showed that hematopoiesis (23). These data show that Lmo2 must function at early stages of in adult mice is dependent on this gene (23). Thus, the gene product is required for all of hematopoiesis (Fig. 2) either at the level of the pluripotent stem cell the stages of adult hematopoiesis, functioning at least before the bifurcation of myeloid and lymphoid lineages. The function may be restricted to the bone marrow stem cell or even perhaps before this when ventral mesoderm gives rise to these (either at the self-renewal stage or at the proliferative stages that produce committed precursor cells. Remarkably similar results have been shown for progenitors) or in the ventral mesoderm bone marrow precursor cells. another T-cell oncogene, Tall/Scl (herein called Tall; Refs. (24-27). The notion of genes that function in developmental processes is clearly delineated by the Lmo2 gene. LDB1 interact in vivo in T-ALL and in neuroblastoma cell lines (41). LMO2 Functions by Protein Interaction: The Role of the LIM This array of interactions led to the observation that Lmo2 is found in Domain. The concept that oncogenes can interfere with developmen- an oligomeric complex in erythroid cells that involves--in addition to tal processes because they are themselves normally performing this Lmo2--Tall, E47, Ldbl and Gata-I (40). This complex is able to function has been suggested to explain their role in tumor etiology. bind DNA at least in vitro and in reporter assays, with the Lmo2 and The finding that genes that encode proteins such as Lmo2 control Ldbl components seeming to bridge a bipartite DNA-binding com- development of hematopoietic lineages led to clear tests of molecular plex (Fig. 3A). These findings suggest that Lmo2 is part of a tran- function in both normal and tumor contexts.
Load more

Recommended publications
  • ARID5B As a Critical Downstream Target of the TAL1 Complex That Activates the Oncogenic Transcriptional Program and Promotes T-Cell Leukemogenesis
    Downloaded from genesdev.cshlp.org on October 10, 2021 - Published by Cold Spring Harbor Laboratory Press ARID5B as a critical downstream target of the TAL1 complex that activates the oncogenic transcriptional program and promotes T-cell leukemogenesis Wei Zhong Leong,1 Shi Hao Tan,1 Phuong Cao Thi Ngoc,1 Stella Amanda,1 Alice Wei Yee Yam,1 Wei-Siang Liau,1 Zhiyuan Gong,2 Lee N. Lawton,1 Daniel G. Tenen,1,3,4 and Takaomi Sanda1,4 1Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore; 2Department of Biological Sciences, National University of Singapore, 117543 Singapore; 3Harvard Medical School, Boston, Massachusetts 02215, USA; 4Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore The oncogenic transcription factor TAL1/SCL induces an aberrant transcriptional program in T-cell acute lym- phoblastic leukemia (T-ALL) cells. However, the critical factors that are directly activated by TAL1 and contribute to T-ALL pathogenesis are largely unknown. Here, we identified AT-rich interactive domain 5B (ARID5B) as a col- laborating oncogenic factor involved in the transcriptional program in T-ALL. ARID5B expression is down-regulated at the double-negative 2–4 stages in normal thymocytes, while it is induced by the TAL1 complex in human T-ALL cells. The enhancer located 135 kb upstream of the ARID5B gene locus is activated under a superenhancer in T-ALL cells but not in normal T cells. Notably, ARID5B-bound regions are associated predominantly with active tran- scription. ARID5B and TAL1 frequently co-occupy target genes and coordinately control their expression.
    [Show full text]
  • LMO T-Cell Translocation Oncogenes Typify Genes Activated by Chromosomal Translocations That Alter Transcription and Developmental Processes
    Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes Terence H. Rabbitts1 Medical Research Council (MRC) Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Cambridge CB2 2QH, UK The cytogenetic analysis of tumors, particularly those of ment (immunoglobulin or T-cell receptor) occurs and oc- hematopoietic origin, has revealed that reciprocal chro- casionally mediates chromosomal translocation. This mosomal translocations are recurring features of these type of translocation causes oncogene activation result- tumors. Further from the initial recognition of the trans- ing from the new chromosomal environment of the re- location t(9;22) (Nowell and Hungerford 1960; Rowley arranged gene. In general, this means inappropriate gene 1973), it has become clear that particular chromosomal expression. The second, and probably the most common translocations are found consistently in specific tumor outcome of chromosomal translocations, is gene fusion subtypes. A principle example of this is the translocation in which exons from a gene on each of the involved chro- t(8;14)(q24;q32.1) invariably found in the human B cell mosomes are linked after the chromosomal transloca- tumor Burkitt’s lymphoma (Manolov and Manolov 1972; tion, resulting in a fusion mRNA and protein. This type Zech et al. 1976). The link with the immunoglobulin of event is found in many cases of hematopoietic tumors H-chain locus on chromosome 14, band q32.1 (Croce et and in the sarcomas. al. 1979; Hobart et al.
    [Show full text]
  • SHQ1 Regulation of RNA Splicing Is Required for T-Lymphoblastic Leukemia Cell Survival
    ARTICLE DOI: 10.1038/s41467-018-06523-4 OPEN SHQ1 regulation of RNA splicing is required for T-lymphoblastic leukemia cell survival Hexiu Su1,2, Juncheng Hu2, Liang Huang 3, Yang Yang4, Morgan Thenoz5, Anna Kuchmiy6, Yufeng Hu7, Peng Li 8, Hui Feng 9, Yu Zhou 4, Tom Taghon6, Pieter Van Vlierberghe 5, Guoliang Qing 2,7, Zhichao Chen1 & Hudan Liu2,7 T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy with 1234567890():,; complicated heterogeneity. Although expression profiling reveals common elevated genes in distinct T-ALL subtypes, little is known about their functional role(s) and regulatory mechanism(s). We here show that SHQ1, an H/ACA snoRNP assembly factor involved in snRNA pseudouridylation, is highly expressed in T-ALL. Mechanistically, oncogenic NOTCH1 directly binds to the SHQ1 promoter and activates its transcription. SHQ1 depletion induces T-ALL cell death in vitro and prolongs animal survival in murine T-ALL models. RNA-Seq reveals that SHQ1 depletion impairs widespread RNA splicing, and MYC is one of the most prominently downregulated genes due to inefficient splicing. MYC overexpression sig- nificantly rescues T-ALL cell death resulted from SHQ1 inactivation. We herein report a mechanism of NOTCH1–SHQ1–MYC axis in T-cell leukemogenesis. These findings not only shed light on the role of SHQ1 in RNA splicing and tumorigenesis, but also provide additional insight into MYC regulation. 1 Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 2 Medical Research Institute, Wuhan University, Wuhan 430071, China. 3 Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
    [Show full text]
  • The TAL1 Complex Targets the FBXW7 Tumor Suppressor by Activating Mir-223 in Human T Cell Acute Lymphoblastic Leukemia
    Article The TAL1 complex targets the FBXW7 tumor suppressor by activating miR-223 in human T cell acute lymphoblastic leukemia Marc R. Mansour,1,3 Takaomi Sanda,1,4 Lee N. Lawton,5 Xiaoyu Li,2 Taras Kreslavsky,2 Carl D. Novina,2,6 Marjorie Brand,7,8 Alejandro Gutierrez,1,9 Michelle A. Kelliher,10 Catriona H.M. Jamieson,11 Harald von Boehmer,2 Richard A. Young,5,12 and A. Thomas Look1,9 Downloaded from http://rupress.org/jem/article-pdf/210/8/1545/1211584/jem_20122516.pdf by guest on 30 September 2021 1Department of Pediatric Oncology and 2Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02216 3Department of Haematology, University College London Cancer Institute, University College London, WC1E 6BT, England, UK 4Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599 5Whitehead Institute for Biomedical Research, , Cambridge, MA 02142 6Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142 7The Sprott Center for Stem Cell Research, Department of Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario K1Y 4E9, Canada 8Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada 9Division of Hematology/Oncology, Children’s Hospital, Boston, MA 02115 10Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605 11Department of Medicine and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 12Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142 The oncogenic transcription factor TAL1/SCL is aberrantly expressed in 60% of cases of human T cell acute lymphoblastic leukemia (T-ALL) and initiates T-ALL in mouse models.
    [Show full text]
  • Expression of LIM Protein Genes Lmo1, Lmo2, and Lmo3 in Adult Mouse Hippocampus and Other Forebrain Regions: Differential Regulation by Seizure Activity
    The Journal of Neuroscience, July 15, 1997, 17(14):5549–5559 Expression of LIM Protein Genes Lmo1, Lmo2, and Lmo3 in Adult Mouse Hippocampus and Other Forebrain Regions: Differential Regulation by Seizure Activity G. L. Hinks,1,2 B. Shah,2 S. J. French,1,3 L. S. Campos,1,3 K. Staley,3 J. Hughes,2 and M. V. Sofroniew1,3 1Medical Research Council Cambridge Centre for Brain Repair, Forvie Site, Cambridge CB2 2PY, United Kingdom, 2Parke-Davis Neuroscience Research Centre, Forvie Site, Cambridge CB2 2QB, United Kingdom, and 3Department of Anatomy, University of Cambridge, Cambridge CB2 3DY, United Kingdom The LIM domain is a zinc-binding amino acid motif that char- tion, Lmo1, Lmo2, and Lmo3 show different combinatorial pat- acterizes various proteins which function in protein–protein terns of expression levels in CA pyramidal and dentate granule interactions and transcriptional regulation. Expression patterns neurons, and Lmo1 is present in topographically restricted of several LIM protein genes are compatible with roles in ver- subpopulations of astrocytes. Kainic acid-induced limbic sei- tebrate CNS development, but little is known about the expres- zures differentially regulated Lmo1, Lmo2, and Lmo3 mRNA sion, regulation, or function of LIM proteins in the mature CNS. levels in hippocampal pyramidal and granule neurons, such that Lmo1, Lmo2, and Lmo3 are LIM-only genes originally identified Lmo1 mRNA increased, whereas Lmo2 and Lmo3 mRNAs as putative oncogenes that have been implicated in the control decreased significantly, with maximal changes at 6 hr after of cell differentiation and are active during CNS development. seizure onset and return to baseline by 24 hr.
    [Show full text]
  • Genehancer: Genome-Wide Integration of Enhancers and Target
    Database, 2017, 1–17 doi: 10.1093/database/bax028 Original article Original article GeneHancer: genome-wide integration of enhancers and target genes in GeneCards Simon Fishilevich1,†, Ron Nudel1,†, Noa Rappaport1, Rotem Hadar1, Inbar Plaschkes1, Tsippi Iny Stein1, Naomi Rosen1, Asher Kohn2, Michal Twik1, Marilyn Safran1, Doron Lancet1,* and Dana Cohen1,* 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel and 2LifeMap Sciences Inc, Marshfield, MA 02050, USA *Corresponding author: Tel: +972-54-4682521; Fax: +972-8-9344487. Email: [email protected] Correspondence may also be addressed to Dana Cohen. Email: [email protected] †These authors contributed equally to this work. Citation details: Fishilevich,S., Nudel,R., Rappaport,N. et al. GeneHancer: genome-wide integration of enhancers and tar- get genes in GeneCards. Database (2017) Vol. 2017: article ID bax028; doi:10.1093/database/bax028 Received 15 November 2016; Revised 9 March 2017; Accepted 10 March 2017 Abstract A major challenge in understanding gene regulation is the unequivocal identification of enhancer elements and uncovering their connections to genes. We present GeneHancer, a novel database of human enhancers and their inferred target genes, in the framework of GeneCards. First, we integrated a total of 434 000 reported enhancers from four different genome-wide databases: the Encyclopedia of DNA Elements (ENCODE), the Ensembl regulatory build, the functional annotation of the mammalian genome (FANTOM) project and the VISTA Enhancer Browser. Employing an integration algorithm that aims to re- move redundancy, GeneHancer portrays 285 000 integrated candidate enhancers (cover- ing 12.4% of the genome), 94 000 of which are derived from more than one source, and each assigned an annotation-derived confidence score.
    [Show full text]
  • Characterization of a Pediatric T-Cell Acute Lymphoblastic Leukemia Patient with Simultaneous LYL1 and LMO2 Rearrangements
    Articles and Brief Reports Acute Lymphoblastic Leukemia Characterization of a pediatric T-cell acute lymphoblastic leukemia patient with simultaneous LYL1 and LMO2 rearrangements Irene Homminga, 1 Maartje J. Vuerhard, 1 Anton W. Langerak, 2 Jessica Buijs-Gladdines, 1 Rob Pieters, 1 and Jules P.P. Meijerink 1 1Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children’s Hospital, Rotterdam; and 2Department of Immunology, Erasmus MC, Rotterdam, The Netherlands ABSTRACT Translocation of the LYL1 oncogene are rare in T-cell acute consistently clustered along with cases having TAL1 or lymphoblastic leukemia, whereas the homologous TAL1 LMO2 rearrangements. Therefore, LYL1 -rearranged cases are gene is rearranged in approximately 20% of patients. not necessarily associated with immature T-cell develop - Previous gene-expression studies have identified an imma - ment, despite high LYL1 levels, but elicit a TALLMO expres - ture T-cell acute lymphoblastic leukemia subgroup with high sion signature. LYL1 expression in the absence of chromosomal aberrations. Molecular characterization of a t(7;19)(q34;p13) in a pediatric Key words: T-ALL, pediatric, LYL1, LMO2, rearrangements. T-cell acute lymphoblastic leukemia patient led to the identi - fication of a translocation between the TRB@ and LYL1 loci. Citation: Homminga I, Vuerhard MJ, Langerak AW, Buijs- Similar to incidental T-cell acute lymphoblastic leukemia Gladdines J, Pieters R, and Meijerink JPP. Characterization of a cases with synergistic, double translocations affecting pediatric T-cell acute lymphoblastic leukemia patient with simul - TAL1/2 and LMO1/2 oncogenes, this LYL1 -translocated taneous LYL1 and LMO2 rearrangements. Haematologica patient also had an LMO2 rearrangement pointing to onco - 2012;97(2):258-261.
    [Show full text]
  • LMO1 Functions As an Oncogene by Regulating TTK Expression and Correlates with Neuroendocrine Differentiation of Lung Cancer
    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 51), pp: 29601-29618 Research Paper LMO1 functions as an oncogene by regulating TTK expression and correlates with neuroendocrine differentiation of lung cancer Liqin Du1, Zhenze Zhao1, Milind Suraokar2, Spencer S. Shelton1, Xiuye Ma3, Tzu-Hung Hsiao4, John D. Minna5, Ignacio Wistuba2,6 and Alexander Pertsemlidis3,7 1Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas, USA 2Departments of Pathology and Thoracic/Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, Texas, USA 3Greehey Children’s Cancer Research Institute, UT Health Science Center at San Antonio, San Antonio, Texas, USA 4Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan 5Hamon Center for Therapeutic Oncology Research and Departments of Pharmacology and Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas, USA 6Department of Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, Texas, USA 7Departments of Pediatrics and Cell Systems & Anatomy, UT Health Science Center at San Antonio, San Antonio, Texas, USA Correspondence to: Liqin Du, email: [email protected] Alexander Pertsemlidis, email: [email protected] Keywords: LMO1; lung cancer; neuroendocrine; TTK Received: February 07, 2017 Accepted: May 24, 2018 Published: July 03, 2018 Copyright: Du et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT LMO1 encodes a protein containing a cysteine-rich LIM domain involved in protein–protein interactions. Recent studies have shown that LMO1 functions as an oncogene in several cancer types, including non-small cell lung cancer (NSCLC).
    [Show full text]
  • Retinoic Acid Rewires the Adrenergic Core Regulatory Circuitry of Neuroblastoma but Can Be Subverted by Enhancer Hijacking of MY
    bioRxiv preprint doi: https://doi.org/10.1101/2020.07.23.218834; this version posted July 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN Mark W. Zimmerman1†, Adam D. Durbin1, Shuning He1, Felix Oppel1, Hui Shi1, Ting Tao1, Zhaodong Li1, Alla Berezovskaya1, Yu Liu2, Jinghui Zhang2, Richard A. Young3,4, Brian J. Abraham2, A. Thomas Look1† 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215 2 Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105 3 Whitehead Institute, Cambridge, MA, 02142 4 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02142 †Email: [email protected] (M.W.Z.) and [email protected] (A.T.L.) Keywords: Neuroblastoma, transcription, retinoic acid, enhancer hijacking Running title: Retinoic acid rewires the core regulatory circuitry of neuroblastoma 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.07.23.218834; this version posted July 24, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ABSTRACT Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program.
    [Show full text]
  • Integrated Functional Genomic Analysis Enables Annotation of Kidney Genome-Wide Association Study Loci
    BASIC RESEARCH www.jasn.org Integrated Functional Genomic Analysis Enables Annotation of Kidney Genome-Wide Association Study Loci Karsten B. Sieber,1 Anna Batorsky,2 Kyle Siebenthall,2 Kelly L. Hudkins,3 Jeff D. Vierstra,2 Shawn Sullivan,4 Aakash Sur,4,5 Michelle McNulty,6 Richard Sandstrom,2 Alex Reynolds,2 Daniel Bates,2 Morgan Diegel,2 Douglass Dunn,2 Jemma Nelson,2 Michael Buckley,2 Rajinder Kaul,2 Matthew G. Sampson,6 Jonathan Himmelfarb,7,8 Charles E. Alpers,3,8 Dawn Waterworth,1 and Shreeram Akilesh3,8 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background Linking genetic risk loci identified by genome-wide association studies (GWAS) to their causal genes remains a major challenge. Disease-associated genetic variants are concentrated in regions con- taining regulatory DNA elements, such as promoters and enhancers. Although researchers have previ- ously published DNA maps of these regulatory regions for kidney tubule cells and glomerular endothelial cells, maps for podocytes and mesangial cells have not been available. Methods We generated regulatory DNA maps (DNase-seq) and paired gene expression profiles (RNA-seq) from primary outgrowth cultures of human glomeruli that were composed mainly of podo- cytes and mesangial cells. We generated similar datasets from renal cortex cultures, to compare with those of the glomerular cultures. Because regulatory DNA elements can act on target genes across large genomic distances, we also generated a chromatin conformation map from freshly isolated human glomeruli. Results We identified thousands of unique regulatory DNA elements, many located close to transcription factor genes, which the glomerular and cortex samples expressed at different levels.
    [Show full text]
  • OLIG2 (BHLHB1), a Bhlh Transcription Factor, Contributes to Leukemogenesis in Concert with LMO1
    Research Article OLIG2 (BHLHB1), a bHLH Transcription Factor, Contributes to Leukemogenesis in Concert with LMO1 Ying-Wei Lin,1 Ramona Deveney,1 Mary Barbara,2 Norman N. Iscove,2 Stephen D. Nimer,3 Christopher Slape,1 and Peter D. Aplan1 1Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland; 2Department of Medical Biophysics, University of Toronto, Ontario, Canada; and 3Department of Medicine, Hematology Service, Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York Abstract differentiation and specification (5–9). More recently, it has been OLIG2 (originally designated BHLHB1) encodes a transcrip- shown that human OLIG genes, including OLIG1 (BHLHB2) and tion factor that contains the basic helix-loop-helix motif. OLIG2 (BHLHB1), are overexpressed in oligodendroglioma, in Although expression of OLIG2 is normally restricted to neural contrast to the low level or absent expression seen in astrocytoma tissues, overexpression of OLIG2 has been shown in patients samples (10, 11). This is an important clinical finding because with precursor T-cell lymphoblastic lymphoma/leukemia there has been a lack of molecular markers that histologically (pre-T LBL). In the current study, we found that over- clearly distinguish oligodendroglioma from astrocytoma. expression of OLIG2 was not only found in oligodendroglioma The human OLIG2 gene was originally identified by virtue of its samples and normal neural tissue but also in a wide spectrum activation by chromosomal translocation in a precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) patient with a of malignant cell lines including leukemia, non–small cell lung carcinoma, melanoma, and breast cancer cell lines.
    [Show full text]
  • Modeling T-Cell Acute Lymphoblastic Leukemia Induced by the SCL and LMO1 Oncogenes
    Downloaded from genesdev.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Modeling T-cell acute lymphoblastic leukemia induced by the SCL and LMO1 oncogenes Mathieu Tremblay,1,7 Ce´dric S. Tremblay,1,7 Sabine Herblot,1,8 Peter D. Aplan,2 Jose´eHe´bert,3 Claude Perreault,1 and Trang Hoang1,4,5,6,9 1Institute of Research in Immunology and Cancer, University of Montreal, Montre´al, Que´bec H3C 3J7, Canada; 2Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA; 3Banque de Cellules Leuce´miques du Que´bec, Maisonneuve-Rosemont Hospital, Montre´al, Que´bec H1T 2M4, Canada; 4Department of Pharmacology, Faculty of Medicine, University of Montre´al, Montre´al, Que´bec H3C 3J7, Canada; 5Department of Biochemistry, Faculty of Medicine, University of Montre´al, Montre´al, Que´bec H3C 3J7, Canada; 6Department of Molecular Biology, Faculty of Medicine, University of Montre´al, Montre´al, Que´bec H3C 3J7, Canada Deciphering molecular events required for full transformation of normal cells into cancer cells remains a challenge. In T-cell acute lymphoblastic leukemia (T-ALL), the genes encoding the TAL1/SCL and LMO1/2 transcription factors are recurring targets of chromosomal translocations, whereas NOTCH1 is activated in >50% of samples. Here we show that the SCL and LMO1 oncogenes collaborate to expand primitive thymocyte progenitors and inhibit later stages of differentiation. Together with pre-T-cell antigen receptor (pre-TCR) signaling, these oncogenes provide a favorable context for the acquisition of activating Notch1 mutations and the emergence of self-renewing leukemia-initiating cells in T-ALL.
    [Show full text]