DOCSLIB.ORG

Late-Breaking Oral Presentations

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Late-Breaking Oral Presentations LATE-BREAKING ORAL PRESENTATIONS 2006 – VIAGRA ENABLES EFFICIENT, SINGLE-DAY HEMATOPOIETIC STEM CELL MOBILIZATION Stephanie Smith-Berdan; Bryan Petkus; Alyssa Bercassio; Camilla Forsberg UCSC, Santa Cruz, United States Despite the use of hematopoietic stem cells (HSCs) in clinical therapy for over half a century, the mechanisms regulating HSC trafficking, engraftment, and life-long persistence after transplantation are unclear. Findings over the past several years have demonstrated that HSC function within bone marrow (BM) niches depends on vascular and peri-vascular cells. We recently showed that the vascular endothelium not only regulates HSC maintenance within BM niches, but also trafficking between the vasculature and the BM space. We found that the vascular endothelium, via the guidance molecule ROBO4, reinforces HSC localization to BM niches both by promoting HSC extravasation from blood-to-BM and by forming vascular barriers that prevent BM-to-blood escape. As ROBO4 promotes vascular stability, we hypothesized that vascular permeability regulates HSC location. We found that vascular permeability induced by intravenous injection of recombinant VEGF led to a 2-fold increase in HSCs in the peripheral blood. Here, we utilized a tet-inducible VEGF overexpression mouse model to show that sustained VEGF expression and robust vascular permeability leads to unprecedented HSC mobilization. VEGF-mediated mobilization was transient and reversible and did not irrevocably damage BM vascular niches. These findings revealed that vascular integrity is an important regulator of HSC location and that manipulation of vascular integrity can be employed to control HSC mobilization. We therefore tested whether FDA-approved vasodilators are capable of mobilizing HSCs. We found that a single, oral dose of Viagra (sildenafil citrate) in conjunction with a single dose of the CXCR4 antagonist AMD3100 leads to efficient HSC mobilization at levels rivaling a 4- day GCSF regimen. Our findings solidify vascular integrity as an essential regulator of HSC trafficking and provide an attractive new, single-day regimen for HSC mobilization using already FDA-approved drugs. 2016 – HUMAN HEMATOPOIETIC STEM CELL SELF-RENEWAL AND ENGRAFTMENT ARE ENHANCED BY THE TRANSCRIPTIONAL REGULATOR MLLT3 Vincenzo Calvanese1; Anastasia Vavilina2; Andrew Nguyen2; Timothy Bolan2; Fides Lay2; Siavash Kurdistani2; Mattias Magnusson2; Hanna Mikkola2 1University of California, Los Angeles, Los Angeles, United States; 2UCLA, Los Angeles, United States Hematopoietic stem cells (HSC) regenerate the blood and immune system upon transplantation, providing treatment for several blood diseases. However, HSC transplantation is available for only a fraction of patients due to limitations in availability and/or histocompatibility. To achieve robust HSC expansion for transplantation we need to understand the mechanisms governing self-renewal, and why this program fails in culture. Through transcriptional profiling of highly self-renewing human HSC and their differentiated or cultured progeny, we identified MLLT3 as a critical HSC regulator, enriched in human fetal and adult HSC, but downregulated during culture. Knockdown of MLLT3 disrupted the expansion and engraftment of hematopoietic stem/progenitor cells (HSPC). Conversely, sustaining MLLT3 expression in culture led to expansion of HSPC with multilineage differentiation ability and superior engraftment capacity. Engraftment of MLLT3-expressing cultured HSPC was 14-30 fold higher than controls; it was detected for 24 weeks and further maintained in secondary transplantation. MLLT3-expanded HSPC displayed repopulation of the HSPC compartment and all differentiated lineages in bone marrow and peripheral hematopoietic organs. Moreover, HSPC cultured for 2 weeks in presence of MLLT3 showed more effective human engraftment compared to those transplanted before culture expansion. Importantly, MLLT3 did not reprogram progenitors to HSC, or cause oncogenic transformation. Similar to endogenous MLLT3, overexpressed MLLT3 localized to promoters of genes expressed in HSPC, and stabilized HSC regulatory program in culture. MLLT3 maintained other key HSC regulators, such as HLF and MECOM, through direct binding, and indirectly suppressed abnormal activation of immune response and apoptosis genes in cultured HSPC. HSC genes in MLLT3 expanded HSPC featured higher levels of the transcriptional activation mark H3K79me2, deposited by the MLLT3 interaction partner Dot1L. MLLT3 thus represents a novel HSC maintenance factor that links histone reader and modifying activities to fine-tune HSC genes, and introduces a promising approach to culture HSC for therapeutic applications. LATE-BREAKING POSTER PRESENTATIONS 3207 – CD97 IS ASSOCIATED WITH POOR OVERALL SURVIVAL IN ACUTE MYELOID LEUKEMIA Houda Alachkar,1; Vijaya Vaikari; Sharon Wu USC, Los Angeles, United States In the era of precision medicine, the treatment of Acute Myeloid Leukemia (AML) remains a significant challenge with fewer than 50% of patients having long-term disease-free survival. Here we take advantage of the large genomics data to explore the expression of particular genes to establish the rationale for further investigation of these genes as viable therapeutic targets in AML. CD97, a member of the adhesion G protein-coupled receptor (GPCR) is expressed on leukocytes and smooth muscles. CD97 is also expressed in a variety of solid cancers and support a more aggressive metastatic phenotype. In this report, we analyzed 170 patients from the TCGA AML dataset and found that CD97 was higher in cytogenetically normal (CN-AML) patients compared with cytogenetically abnormal (CA-AML) patients (p=0.008). We dichotomized patients based on their CD97 mRNA expression Z-score (RNA Seq V2 RSEM) into CD97 high (Z≥1) and CD97 low (Z<1). Patients with high CD97 expression had significantly higher WBC count (median: 52.9 vs 12.6, p=0.005) and higher % bone marrow blasts (median: 83 vs 71%, p=0.025). We also analyzed CD97 expression according to mutational status and found that CD97 was significantly higher in patients with NPM1 mutation (n=47) compared with that in patients with NPM1 wild- type (n=123) (1.6 fold, p<0.000). Survival analysis showed that the overall survival (OS) of the CD97 high group (Z >1) was significantly shorter than those of the CD97 low patients (median: 7.2 vs. 21.1 months; p=0.0003; Figure 4A). Patients with high CD97 expression had significantly shorter event-free survival (EFS) than patients with low CD97 (median: 5.3 vs. 12 months; p=0.0003). In multivariate survival analysis, CD97 high expression (Z>1) was associated with shorter overall survival when adjusted for age, white blood count, cytogenetic risk, transplant status, DNMT3A mutation status, and TP53 mutation status (HR= 1.86; 95% Cl: 1.10-3.13; p=0.020). Altogether, our results suggest that high CD97 expression is associated with poor clinical outcome and indicate a need for future functional and mechanistic for the role of CD97 in AML. 3208 – REPROGRAMMED ADULT HUMAN ENDOTHELIUM INTO HEMATOPOIETIC STEM CELLS YIELDS FUNCTIONAL T CELLS IN VIVO Jose Gabriel Barcia Duran; Tyler Lu; Raphael Lis; Shahin Rafii Weill Cornell Medicine, New York, United States During development, the hematopoietic stem cells that go on to populate the bone marrow and give rise to all blood cell lineages emerge from a specialized endothelial subpopulation. We have previously exploited this vestigial identity to achieve the direct conversion of adult mouse or human endothelial cells (ECs) into long- term engraftable hematopoietic stem and progenitor cells (rEC-HSPCs); however, to date, we had only detected and characterized functional T cells that result from the transplantation, engraftment, and differentiation of mouse rEC-HSPCs. Here, we make use of doxycycline-inducible vectors encoding our four reprogramming transcription factors (FOSB, GFI1, SPI1, and RUNX1; FGRS). Additionally, transplantation is performed in transgenic substrains of NSG mice (one carrying human stem cell factor, granulocyte/macrophage colony-stimulating factor, and interleukin 3; the other, human major histocompatibility complex class I as well as beta-2 microglobulin). We show that human rEC-HSPCs obtained via our established in vitro system yield phenotypically and functionally mature T cells in vivo at 24 weeks post-transplantation (primary and secondary) when FGRS expression is suspended upon transplantation and the transplant recipients express transgenes for human cytokines or MHC class I proteins. Notably, the resulting T cells undergo TCR rearrangement and are able to clear viral particles one week post- LCMV infection. This achievement demonstrates that our direct conversion strategy generates bona fide human hematopoietic stem cells from adult endothelial cells. 3209 – SOMATIC MUTATIONS IN HEMATOPOIETIC STEM CELLS REVEAL LINEAGE RELATIONSHIPS AND AGE-RELATED MUTAGENESIS Arianne Brandsma1; Fernando Osorio2; Axel Rosendahl Huber1; Rurika Oka1; Mark Verheul1; Sachin Patel2; Lisanne de la Fonteijne3; Ignacio Varela4; Fernando Camargo2; Ruben van Boxtel1 1Princess Maxima Center for pediatric cancer, Utrecht, Netherlands; 2Stem Cell Program, Bosten Children's Hospital, Boston, United States; 3Center for Molecular Medicine, UMC Utrecht, Utrecht, Netherlands; 4IBBTEC, CSIC-University of Cantabria, Santander, Spain Mutation accumulation during human life can contribute to hematopoietic dysfunction; however, the underlying dynamics are unknown. In addition, as people
Load more

Recommended publications
  • Kmt2a-Mllt3 Ioannis Panagopoulos 1, Kristin Andersen 1, Martine Eilert-Olsen 1, Bernward Zeller 2, Monica Cheng Munthe-Kaas 2, Jochen Buechner 2, Liv T.N
    CANCER GENOMICS & PROTEOMICS 18 : 67-81 (2021) doi:10.21873/cgp.20242 Therapy-induced Deletion in 11q23 Leading to Fusion of KMT2A With ARHGEF12 and Development of B Lineage Acute Lymphoplastic Leukemia in a Child Treated for Acute Myeloid Leukemia Caused by t(9;11)(p21;q23)/ KMT2A-MLLT3 IOANNIS PANAGOPOULOS 1, KRISTIN ANDERSEN 1, MARTINE EILERT-OLSEN 1, BERNWARD ZELLER 2, MONICA CHENG MUNTHE-KAAS 2, JOCHEN BUECHNER 2, LIV T.N. OSNES 3, FRANCESCA MICCI 1 and SVERRE HEIM 1,4 1Section for Cancer Cytogenetics, Institute for Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; 2Department of Pediatric Hematology and Oncology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 3Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; 4Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Abstract. Background/Aim: Fusion of histone-lysine N- The histone-lysine N-methyltransferase 2A ( KMT2A , also methyltransferase 2A gene (KMT2A) with the Rho guanine known as MLL ) gene in 11q23 (1, 2) may fuse with more than nucleotide exchange factor 12 gene (ARHGEF12), both located 100 different partners in acute lymphoblastic leukemia (ALL), in 11q23, was reported in some leukemic patients. We report a acute myeloid leukemia (AML), chronic myeloid leukemia, KMT2A-ARHGEF12 fusion occurring during treatment of a myelodysplastic syndromes, lymphomas, and solid tumors (3). pediatric acute myeloid leukemia (AML) with topoisomerase II Some of the resulting chimeras are common, such as the fusions inhibitors leading to a secondary acute lymphoblastic leukemia with the AF4/FMR2 family member 1 ( AFF1 ) and MLLT3 (ALL). Materials and Methods: Multiple genetic analyses were super elongation complex subunit ( MLLT3 ) genes generated by performed on bone marrow cells of a girl initially diagnosed t(4;11)(q21;q23) in ALL ( KMT2A-AFF1 ) and t(9;11)(p21;q23) with AML.
    [Show full text]
  • An Extra Chromosome 9 Derived from Either a Normal
    ONCOLOGY LETTERS 18: 6725-6731, 2019 An extra chromosome 9 derived from either a normal chromosome 9 or a derivative chromosome 9 in a patient with acute myeloid leukemia positive for t(9;11)(p21.3;q23.3): A case report MAN GAO1, HUI PANG2, YOUNG MI KIM2, XIANGLAN LU2, XIANFU WANG2, JIYUN LEE2,3, MINGWEI WANG4, FANZHENG MENG1 and SHIBO LI2 1Department of Pediatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China; 2Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma, OK 73104, USA; 3Department of Pathology, College of Medicine, Korea University, Seoul, South Korea; 4Clinical Medical College of Beihua University, Jilin City, Jilin 132013, P.R. China Received March 11, 2019; Accepted September 27, 2019 DOI: 10.3892/ol.2019.11035 Abstract. Translocation (9;11)(p21.3;q23.3) is one the extra chromosome 9 could serve a crucial role in AML of the most common lysine methyltransferase 2A disease progression and contribute to cellular sensitivity to (KMT2A)-rearrangements in de novo and therapy-related chemotherapy. acute myeloid leukemia (AML). Numerous in vitro and in vivo studies have demonstrated that the KMT2A/MLLT3 Introduction super elongation complex subunit (MLLT3) fusion gene on the derivative chromosome 11 serves a crucial role in leuke- Chromosomal rearrangements of the lysine methyltransferase mogenesis. Trisomy 9 as a secondary chromosome change 2A (KMT2A) gene (former MLL) at 11q23 have been reported in patients with t(9;11) is relatively rare. The present study in ~10% of patients with acute leukemias (1). Analysis of reported a unique case of AML with a chromosome 9 trisomy the KMT2A recombinome of acute leukemias has identified secondary to t(9;11)(p21.3;q23.3) through the cytogenetic 135 totally different KMT2A rearrangements, and 94 related analysis of leukemic blood and bone marrow.
    [Show full text]
  • Mutational Landscape and Clinical Outcome of Patients with De Novo Acute Myeloid Leukemia and Rearrangements Involving 11Q23/KMT2A
    Mutational landscape and clinical outcome of patients with de novo acute myeloid leukemia and rearrangements involving 11q23/KMT2A Marius Billa,1,2, Krzysztof Mrózeka,1,2, Jessica Kohlschmidta,b, Ann-Kathrin Eisfelda,c, Christopher J. Walkera, Deedra Nicoleta,b, Dimitrios Papaioannoua, James S. Blachlya,c, Shelley Orwicka,c, Andrew J. Carrolld, Jonathan E. Kolitze, Bayard L. Powellf, Richard M. Stoneg, Albert de la Chapelleh,i,2, John C. Byrda,c, and Clara D. Bloomfielda,c aThe Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; bAlliance for Clinical Trials in Oncology Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; cDivision of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210; dDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294; eNorthwell Health Cancer Institute, Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY 11042; fDepartment of Internal Medicine, Section on Hematology & Oncology, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157; gDepartment of Medical Oncology, Dana-Farber/Partners Cancer Care, Boston, MA 02215; hHuman Cancer Genetics Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210; and iDepartment of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 Contributed by Albert de la Chapelle, August 28, 2020 (sent for review July 17, 2020; reviewed by Anne Hagemeijer and Stefan Klaus Bohlander) Balanced rearrangements involving the KMT2A gene, located at patterns that include high expression of HOXA genes and thereby 11q23, are among the most frequent chromosome aberrations in contribute to leukemogenesis (14–16).
    [Show full text]
  • A KMT2A-AFF1 Gene Regulatory Network Highlights the Role of Core Transcription Factors and Reveals the Regulatory Logic of Key Downstream Target Genes
    Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Research A KMT2A-AFF1 gene regulatory network highlights the role of core transcription factors and reveals the regulatory logic of key downstream target genes Joe R. Harman,1,7 Ross Thorne,1,7 Max Jamilly,2 Marta Tapia,1,8 Nicholas T. Crump,1 Siobhan Rice,1,3 Ryan Beveridge,1,4 Edward Morrissey,5 Marella F.T.R. de Bruijn,1 Irene Roberts,3,6 Anindita Roy,3,6 Tudor A. Fulga,2,9 and Thomas A. Milne1,6 1MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; 2MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, United Kingdom; 3MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Department of Paediatrics, University of Oxford, Oxford, OX3 9DS, United Kingdom; 4Virus Screening Facility, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DS, United Kingdom; 5Center for Computational Biology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom; 6NIHR Oxford Biomedical Research Centre Haematology Theme, University of Oxford, Oxford, OX3 9DS, United Kingdom Regulatory interactions mediated by transcription factors (TFs) make up complex networks that control cellular behavior. Fully understanding these gene regulatory networks (GRNs) offers greater insight into the consequences of disease-causing perturbations than can be achieved by studying single TF binding events in isolation. Chromosomal translocations of the lysine methyltransferase 2A (KMT2A) gene produce KMT2A fusion proteins such as KMT2A-AFF1 (previously MLL-AF4), caus- ing poor prognosis acute lymphoblastic leukemias (ALLs) that sometimes relapse as acute myeloid leukemias (AMLs).
    [Show full text]
  • Transcriptomic and Epigenomic Characterization of the Developing Bat Wing
    ARTICLES OPEN Transcriptomic and epigenomic characterization of the developing bat wing Walter L Eckalbar1,2,9, Stephen A Schlebusch3,9, Mandy K Mason3, Zoe Gill3, Ash V Parker3, Betty M Booker1,2, Sierra Nishizaki1,2, Christiane Muswamba-Nday3, Elizabeth Terhune4,5, Kimberly A Nevonen4, Nadja Makki1,2, Tara Friedrich2,6, Julia E VanderMeer1,2, Katherine S Pollard2,6,7, Lucia Carbone4,8, Jeff D Wall2,7, Nicola Illing3 & Nadav Ahituv1,2 Bats are the only mammals capable of powered flight, but little is known about the genetic determinants that shape their wings. Here we generated a genome for Miniopterus natalensis and performed RNA-seq and ChIP-seq (H3K27ac and H3K27me3) analyses on its developing forelimb and hindlimb autopods at sequential embryonic stages to decipher the molecular events that underlie bat wing development. Over 7,000 genes and several long noncoding RNAs, including Tbx5-as1 and Hottip, were differentially expressed between forelimb and hindlimb, and across different stages. ChIP-seq analysis identified thousands of regions that are differentially modified in forelimb and hindlimb. Comparative genomics found 2,796 bat-accelerated regions within H3K27ac peaks, several of which cluster near limb-associated genes. Pathway analyses highlighted multiple ribosomal proteins and known limb patterning signaling pathways as differentially regulated and implicated increased forelimb mesenchymal condensation in differential growth. In combination, our work outlines multiple genetic components that likely contribute to bat wing formation, providing insights into this morphological innovation. The order Chiroptera, commonly known as bats, is the only group of To characterize the genetic differences that underlie divergence in mammals to have evolved the capability of flight.
    [Show full text]
  • AF9 (MLLT3) Antibody (C-Term K486) Blocking Peptide Synthetic Peptide Catalog # Bp6190a
    10320 Camino Santa Fe, Suite G San Diego, CA 92121 Tel: 858.875.1900 Fax: 858.622.0609 AF9 (MLLT3) Antibody (C-term K486) Blocking peptide Synthetic peptide Catalog # BP6190a Specification AF9 (MLLT3) Antibody (C-term K486) AF9 (MLLT3) Antibody (C-term K486) Blocking Blocking peptide - Background peptide - Product Information The human AF9 gene is one of the most Primary Accession P42568 common fusion partner genes with the ALL1 Other Accession AF9_HUMAN gene at 11q23 (also called MLL), resulting in the t(9;11)(p22;q23). The AF9 gene is more than 100 kb, and 2 patient breakpoint cluster AF9 (MLLT3) Antibody (C-term K486) Blocking peptide - Additional Information regions (BCRs) have been identified; BCR1 is within intron 4, previously called site A, whereas BCR2 or site B spans introns 7 and 8. Gene ID 4300 Several different structural elements have been identified in AF9, including a colocalizing Other Names in vivo DNA topo II cleavage site and an in vitro Protein AF-9, ALL1-fused gene from DNase I hypersensitive (DNase 1 HS) site in chromosome 9 protein, Myeloid/lymphoid or intron 7 in BCR2. Reversibility experiments mixed-lineage leukemia translocated to chromosome 3 protein, YEATS demonstrated a religation of the topo II domain-containing protein 3, MLLT3, AF9, cleavage sites. In addition, 2 scaffold YEATS3 associated regions (SARs) are located centromeric to the topo II and DNase I HS Target/Specificity cleavage sites and border breakpoint regions The synthetic peptide sequence used to in 2 leukemic cells lines: SAR1 is located in generate the antibody <a href=/product/pr intron 4, whereas SAR2 encompasses parts of oducts/AP6190a>AP6190a</a> was exons 5-7.
    [Show full text]
  • Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience-Dependent Cortical Plasticity
    New Research Development Integrative Analysis of Disease Signatures Shows Inflammation Disrupts Juvenile Experience- Dependent Cortical Plasticity Milo R. Smith1,2,3,4,5,6,7,8, Poromendro Burman1,3,4,5,8, Masato Sadahiro1,3,4,5,6,8, Brian A. Kidd,2,7 Joel T. Dudley,2,7 and Hirofumi Morishita1,3,4,5,8 DOI:http://dx.doi.org/10.1523/ENEURO.0240-16.2016 1Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, 2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, 3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, 4Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, 5Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, 6Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, 7Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and 8Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029 Visual Abstract Throughout childhood and adolescence, periods of heightened neuroplasticity are critical for the development of healthy brain function and behavior. Given the high prevalence of neurodevelopmental disorders, such as autism, identifying disruptors of developmental plasticity represents an essential step for developing strategies for prevention and intervention. Applying a novel computational approach that systematically assessed connections between 436 transcriptional signatures of disease and multiple signatures of neuroplasticity, we identified inflammation as a common pathological process central to a diverse set of diseases predicted to dysregulate Significance Statement During childhood and adolescence, heightened neuroplasticity allows the brain to reorganize and adapt to its environment.
    [Show full text]
  • Interplay Between Cofactors and Transcription Factors in Hematopoiesis and Hematological Malignancies
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies Zi Wang 1,2, Pan Wang2, Yanan Li2, Hongling Peng1, Yu Zhu2, Narla Mohandas3 and Jing Liu2 Hematopoiesis requires finely tuned regulation of gene expression at each stage of development. The regulation of gene transcription involves not only individual transcription factors (TFs) but also transcription complexes (TCs) composed of transcription factor(s) and multisubunit cofactors. In their normal compositions, TCs orchestrate lineage-specific patterns of gene expression and ensure the production of the correct proportions of individual cell lineages during hematopoiesis. The integration of posttranslational and conformational modifications in the chromatin landscape, nucleosomes, histones and interacting components via the cofactor–TF interplay is critical to optimal TF activity. Mutations or translocations of cofactor genes are expected to alter cofactor–TF interactions, which may be causative for the pathogenesis of various hematologic disorders. Blocking TF oncogenic activity in hematologic disorders through targeting cofactors in aberrant complexes has been an exciting therapeutic strategy. In this review, we summarize the current knowledge regarding the models and functions of cofactor–TF interplay in physiological hematopoiesis and highlight their implications in the etiology of hematological malignancies. This review presents a deep insight into the physiological and pathological implications of transcription machinery in the blood system. Signal Transduction and Targeted Therapy (2021) ;6:24 https://doi.org/10.1038/s41392-020-00422-1 1234567890();,: INTRODUCTION by their ATPase subunits into four major families, including the Hematopoiesisisacomplexhierarchicaldifferentiationprocessthat SWI/SNF, ISWI, Mi-2/NuRD, and INO80/SWR1 families.
    [Show full text]
  • CPTC-RTF1-2 (CAB079947) Immunohistochemistry
    CPTC-RTF1-2 (CAB079947) Uniprot ID: Q92541 Protein name: RTF1_HUMAN Full name: RNA polymerase-associated protein RTF1 homolog Function: Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non- phosphorylated and 'Ser-2'- and 'Ser-5'-phosphorylated forms and is involved in transcriptional elongation, acting both indepentently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1- MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 'Lys-4' (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of 'Lys-120' of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3' end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Binds single-stranded DNA. Required for maximal induction of heat-shock genes. Required for the trimethylation of histone H3 'Lys-4' (H3K4me3) on genes involved in stem cell pluripotency; this function is synergistic with CXXC1 indicative for an involvement of a SET1 complex (By similarity).
    [Show full text]
  • Epigenetic Changes in Human Model KMT2A Leukemias Highlight Early Events During Leukemogenesis
    Epigenetic changes in human model KMT2A leukemias highlight early events during leukemogenesis Thomas Milan1, Magalie Celton1, Karine Lagacé1, Élodie Roques1, Safia Safa-Tahar-Henni1, Eva Bresson2,3,4, Anne Bergeron2,3,4, Josée Hebert5,6, Soheil Meshinchi7, Sonia Cellot8, Frédéric Barabé2,3,4, 1,6 Brian T Wilhelm Author contributions: BTW and TM designed the study, analyzed data and drafted the manuscript. TM and KL performed ChIP-seq and ATAC-seq, analysed the data and generated figures. MC performed Methyl-seq experiments, analysed data, generated figures and drafted the manuscript. SS-T-H assisted with the ATAC-seq analysis and generation of figures. KL, ER, EB, and AB helped with molecular biology work, cloning and cell culture. EB, AB and FB generated the model on mice from CD34+ cells. SM provided expression and clinical data for patient samples and JH and SC collected, characterized, and banked the local patient samples used in this study. Affiliations: 1Laboratory for High Throughput Biology, Institute for Research in Immunology and Cancer, Montréal, QC, Canada 2Centre de recherche en infectiologie du CHUL, Centre de recherche du CHU de Québec – Université Laval, Québec City, QC, Canada, 3CHU de Québec – Université Laval – Hôpital Enfant-Jésus; Québec City, QC, Canada; 4Department of Medicine, Université Laval, Quebec City, QC, Canada 5Division of Hematology-Oncology and Leukemia Cell Bank of Quebec, Maisonneuve-Rosemont Hospital, Montréal, QC, Canada, 6Department of Medicine, Université de Montréal, Montréal, QC, Canada, 7Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA 8Department of pediatrics, division of Hematology, Ste-Justine Hospital, Montréal, QC, Canada Running head: Early epigenetic changes in KM3-AML *Correspondence to: Brian T Wilhelm Institute for Research in Immunology and Cancer Université de Montréal P.O.
    [Show full text]
  • (P21;Q23) KMT2A/MLLT3 Jeroen Knijnenburg, H
    Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL INIST-CNRS Leukaemia Section Short Communication t(9;11)(p21;q23) KMT2A/MLLT3 Jeroen Knijnenburg, H. Berna Beverloo Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. [email protected] Published in Atlas Database: March 2016 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0911ID1001.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/66949/03-2016-t0911ID1001.pdf DOI: 10.4267/2042/66949 This article is an update of : t(9;11)(p21;q23) KMT2A/MLLT3. Atlas Genet Cytogenet Oncol Haematol 2016;20(12) Huret JL. t(9;11)(p22;q23). Atlas Genet Cytogenet Oncol Haematol 1997;1(2) This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2016 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Clinics Review on t(9;11)(p21;q23), with data on clinics, Organomegaly, frequent central nervous system and the genes involved. (CNS) involvement, especially in de novo cases; no preceding myelodysplastic phase, unlike classic Keywords therapy related AML with chromosome 5 and/or 7 chromosome 9; chromosome 11; acute myeloid involvement, short interval from initial drug therapy leukemia; KMT2A; MLLT3. (may even be of 1-2 yrs). Patients may present with disseminated intravascular coagulation and may Clinics and pathology have tissue infiltration. Disease Cytology Acute myeloid leukemia (AML). Absence of trilineage dysplasia, unlike classic Phenotype/cell stem origin therapy related AML. Most often found in acute monocytic and Prognosis myelomonocytic leukaemias, although occasionally Survival is described as poor to intermediate, being also seen in AML with or without maturation (WHO superior to AML with other KMT2A translocations.
    [Show full text]
  • Modeling Chromosomes in Mouse to Explore the Function of Genes
    Review Modeling Chromosomes in Mouse to Explore the Function of Genes, Genomic Disorders, and Chromosomal Organization Ve´ronique Brault, Patricia Pereira, Arnaud Duchon, Yann He´rault* ABSTRACT chromosomes using microcell-mediated chromosome transfer (MMCT) offers the opportunity to study the function ne of the challenges of genomic research after the of large genes or clusters of genes and provides more and completion of the human genome project is to more mouse models to study human pathologies such as O assign a function to all the genes and to understand contiguous gene syndromes. In this review, we describe the their interactions and organizations. Among the various panel of techniques available for chromosome engineering in techniques, the emergence of chromosome engineering tools the mouse, some of their applications for studying gene with the aim to manipulate large genomic regions in the function and genomic organization and for modeling human mouse model offers a powerful way to accelerate the diseases, and the implications for future research. discovery of gene functions and provides more mouse models to study normal and pathological developmental processes Chemical and Radiation-Induced Chromosome associated with aneuploidy. The combination of gene Rearrangements targeting in ES cells, recombinase technology, and other Historically, various types of rearrangements including techniques makes it possible to generate new chromosomes deletions, inversions, and reciprocal translocations were carrying specific and defined deletions, duplications, obtained through irradiation or chemical mutagenesis. Such inversions, and translocations that are accelerating functional chromosomal configurations are important tools for looking analysis. This review presents the current status of at recessive lethal mutations in mice [16] or to obtain mouse chromosome engineering techniques and discusses the models of partial aneuploidy.
    [Show full text]