Newcastle University

Introduction

Chromosomal changes frequently yield fusion genes, which are exclusively expressed in tumours. They constitute promising targets for new therapeutic approaches, if these oncogenes were essential for tumour maintenance. Our current interest focuses on translocations associated with acute leukaemia: the translocation t(4;11), which is associated with a therapy-resistant infant leukaemia, and the translocation t(8;21), which is one of the most frequently found chromosomal changes in acute myeloid leukaemia. Using RNA interference, we could demonstrate that the corresponding fusion proteins are essential for leukaemic persistence. Current projects include target gene analyses, and the development of in vivo siRNA delivery approaches.

Roles and Responsibilities

Institute GM Chair
Insitute Deputy Safety Officer

Qualifications

Habilitation (postdoctoral lecture qualification), Eberhard Karls University Tuebingen, Germany, 2002

Dr. rer. nat., Georg August University Goettingen, Germany, 1993

Diploma in Biology, Georg August University Goettingen, Germany, 1990

Previous Positions

Since March 2007 Senior Lecturer for Paediatric Molecular Oncology at the Northern Institute for Cancer Research, Newcastle University, UK

Lecturer in the Dept. of Molecular Biology at the Eberhard Karls University Tübingen, Germany,1997-2007

Research assistant in the Dept. of Molecular Biology at Medical School Hannover, Germany, 1996-1997

Postdoctoral fellow at the Scripps Research Institute in La Jolla, San Diego, California, 1993-1995

Graduate student at the Max Planck Institute for Experimental Medicine in Göttingen, Germany 1990-1993

Diploma student at the Max Planck Institute for Experimental Medicine in Göttingen, Germany, 1989-1990

Memberships

Deutsche Gesellschaft für Gentherapie
European Haematology Association
Gesellschaft für Biochemie und Molekularbiologie
Gesellschaft für Genetik

Languages

German
English

Research Interests

Oncogenic fusion genes

Current Work

Role of AML1/MTG8 (RUNX1/RUNX1T1) in leukaemic persistence
Role of MLL/AF4 (MLL/MLLT2) in leukaemic persistence
Systemic delivery of antileukaemic siRNAs

Esteem Indicators

Reviewer for the Leukaemia Research Fund, Children with Leukaemia, Cancer Research UK, Yorkshire Cancer Research.
Reviewer for Blood, Journal of Drug Targeting, Angewandte Chemie, Journal of Molecular and Cellular Medicine, Oligonucleotides, Cancer Letters, Expert Opinion on Therapeutic Targets, Oncogene, Cancer Investigation.

Funding

Primitive Progenitor/Stem Cells in Philadelphia Chromosome-positive Acute Lymphoblastic Leukaemia; Leukaemia Research Fund; £140,299, 01 Dec 2008 - 30 Nov 2010

The Role of RUNX1/RUNX1T1 in Therapy Induced Leukaemia (PhD studentship); JGW Patterson Foundation; £88,381; 01 Oct 2008 - 30 Sep 2011

The role of MLL/AF4 in Leukaemic Maintenance; Leukaemia Research Fund; £212,884; 01 Sep 2008 - 31 Aug 2011

AML1/MTG8 - an addictive oncogone? Kay Kendall Leukaemia Fund; £112,028; 01 Jul 2008 - 30 Jun 2010

NECCR PhD Studentship; North of England Childrens Cancer Research Fund; £32,242.33; 01 Mar 2007 - 30 Sep 2010

Patents

Eckstein F, Pieken W, Benseler F, Olsen DB, Williams DM, Heidenreich O: Modified ribozymes. 91916858; 23.09.1991

Heidenreich O, Vornlocher H-P, Kreutzer R, Limmer S: Method for inhibiting the expression of a target gene resulting from a chromosome aberration. EP 200300608; 22.01.2003

Heidenreich O, Hadwiger P, Vornlocher H-P: RNAi modulation of MLL-AF4 and uses thereof. US Serial No. 60/635,936; 6.12.2005

• Asbeck AHv, Beyerle A, McNeill H, Bovee-Geurts PH, Lindberg S, Verdurmen WPR, Hällbrink M, Langel U, Heidenreich O, Brock R. A Definition of the Molecular Parameters for the Formation of Transfection-Effective siRNA-Cell-Penetrating Peptide Nanoparticles. ACS Nano 2013. In Press.
• Bomken S, Buechler L, Rehe K, Ponthan F, Elder A, Blair H, Bacon CM, Vormoor J, Heidenreich O. Lentiviral marking of patient-derived acute lymphoblastic leukaemic cells allows in vivo tracking of disease progression. Leukemia 2013, 27(3), 718-721.
• Ptasinska A, Assi SA, Mannari D, James SR, Williamson D, Dunne J, Hoogenkamp M, Wu M, Care M, McNeill H, Cauchy P, Cullen M, Tooze RM, Tenen DG, Young BD, Cockerill PN, Westhead DR, Heidenreich O, Bonifer C. Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding. Leukemia 2012, 26, 1829-1841.
• Duque-Afonso J, Yalcin A, Berg T, Abdelkarim M, Heidenreich O, Lübbert M. The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ET. Oncogene 2011, 30(27), 3062-3072.
• Grinev VV, Posrednik DV, Heidenreich O. Effective and specific control of aml1/eto gene expression in acute myeloid leukemia cells by lentivector-based RNA-interference. Molecular Biology 2011, 45(2), 300-308.
• Dunne J, Gascoyne DM, Lister TA, Brady HJ, Heidenreich O, Young BD. AML1/ETO proteins control POU4F1/BRN3A expression and function in t(8;21) acute myeloid leukemia. Cancer Research 2010, 70(10), 3985-3995.
• Bomken S, Fiser K, Heidenreich O, Vormoor J. Understanding the cancer stem cell. British Journal of Cancer 2010, 103(4), 439-445.
• Gessner A, Thomas M, Garrido Castro P, Büchler L, Scholz A, Brümmendorf TH, Martinez Soria N, Vormoor J, Greil J, Heidenreich O. Leukemic fusion genes MLL/AF4 and AML1/MTG8 support leukemic self-renewal by controlling expression of the telomerase subunit TERT. Leukemia 2010, 24(10), 1751-1759.
• Werth D, Grassi G, Konjer N, Dapas B, Farra R, Giansante C, Kandolf R, Guarnieri G, Nordheim A, Heidenreich O. Proliferation of human primary vascular smooth muscle cells depends on serum response factor. European Journal of Cell Biology 2010, 89(2-3), 216-224.
• Osman D, Gobert V, Ponthan FM, Heidenreich O, Haenlin M, Waltzer L. A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO. Proceedings of the National Academy of Sciences of the United States of America 2009, 106(29), 12043-12048.
• Russell LJ, Capasso M, Vater I, Akasaka T, Bernard OA, Calasanz MJ, Chandrasekaran T, Chapiro E, Gesk S, Griffiths M, Guttery DS, Haferlach C, Harder L, Heidenreich O, Irving JAE, Kearney L, Nguyen-Khac F, Machado L, Minto L, Majid A, Moorman AV, Morrison H, Rand V, Strefford JC, Schwab CJ, Tonnies H, Dyer MJ, Siebert R, Harrison CJ. Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B cell precursor acute lymphoblastic leukemia. Blood 2009, 114(13), 2688-2698.
• Martinez Soria N, Tussiwand R, Ziegler P, Manz MG, Heidenreich O. Transient depletion of RUNX1/RUNX1T1 by RNA interference delays tumour formation in vivo. Leukemia 2008, 23(1), 188-190.
• Thomas M, Gessner A, Vornlocher HP, Hadwiger P, Greil J, Heidenreich O. Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells. Blood 2005, 106(10), 3559-3566.
• Martinez N, Drescher B, Riehle H, Cullmann C, Vornlocher HP, Ganser A, Heil G, Nordheim A, Krauter J, Heidenreich O. The oncogenic fusion protein RUNX1-CBFA2T1 supports proliferation and inhibits senescence in t(8;21)-positive leukaemic cells. BMC Cancer 2004, 4(1), 44.
• Heidenreich O, Krauter J, Riehle H, Hadwiger P, John M, Heil G, Vornlocher HP, Nordheim A. AML1/MTG8 oncogene suppression by small interfering RNAs supports myeloid differentiation of t(8;21)-positive leukemic cells. Blood 2003, 101(8), 3157-3163.
• Scherr M, Battmer K, Winkler T, Heidenreich O, Ganser A, Eder M. Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood 2003, 101(4), 1566-1569.
• Rehe K, Wilson K, Bomken S, Williamson D, Irving J, den Boer ML, Stanulla M, Schrappe M, Hall AG, Heidenreich O, Vormoor J. Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations. EMBO Molecular Medicine 2013, 5(1), 38-51.