Laboratory of Lymphocyte Signaling and Oncoproteome

The work of our laboratory centers around the pathogenetic mechanisms in lymphatic malignancies of T-cell and B-cell lineage. Current progress in these tumors towards improved treatment regimens that target relevant molecular mechanisms of tumor cell survival and growth is hampered by our limited understanding of critical transforming and progression pathways including their chronological sequence and hierarchy of dependence at the stage of overt diagnosed disease. Malignant tumors of the lymphatic system, the lymphomas and their pattern subset of lymphatic leukemias, are derived from particular stages of lymphocyte development and preserve many of the precursor cell’s activation pathways, i.e. those mediated through cytokine or antigen receptors, however, often in a dysregulated fashion.

We are constantly seeking enthusiastic PhD students, MD students and postdocs who would like to get involved in our research.

Currently we are searching for a highly motivated postdoc with experience in T-cell-biology.

Please inquire at: marco.herling@uk-koeln.de

Zur Person

English

Kurzbiografie

Dr. med. Marco Herling absolvierte sein Studium der Humanmedizin an der Martin-Luther-Universität Halle-Wittenberg (MLU) von 1992-1999. Im Rahmen eines vom "Biomedical Sciences Exchange Program" geförderten 2-semestrigen integrierten Auslandsstudiums arbeitete Dr. Herling von 1997-1998 am M.D. Anderson Cancer Center (MDACC) Department of Lymphoma and Myeloma an der Etablierung prognostischer Markermodelle zum großzellig anaplastischen T-Zell Lymphom (ALCL) und dem Hodgkin Lymphom. Seine Promotion zum Dr. med. am Pathologischen Institut der MLU zwischen 1994 - 1999 beschrieben präsarkomatöse Veränderungen sowie Tumor-Wirt Interaktionen im chronologischen Längsschnitt experimentell induzierter mesenchymaler Tumoren (Sarkome) der Ratte auf der Basis von zellulären Glykoprotein-Rezeptor Profilen.

Seine klinische Ausbildung begann Dr. Herling in 2000 an der Abteilung Innere Medizin I der Universitätsklinik Freiburg. In 2002 begann Dr. Herling sein Postdoctoral Fellowship im MDACC Department of Hematopathology zu pathogenetischen Mechanismen in T-Zell Neoplasien. Als Absolvent des NIH Physician Scientist PhD Programms (2002 - 2005) konnte Dr. Herling Aspekte seiner laborexperimentellen Arbeiten in klinische Studiendesigns zu lymphozytären Leukämien übertragen (Thesis “Adaptive Randomization and Bayesian statistics”). Als Träger des MDACC Odyssey Special Fellow Award von 2004 - 2006 erweiterte Dr. Herling seine Untersuchungen zu Antigenrezeptor vermittelten Mechanismen in B-Zell und T-Zell Neoplasien.

Mit einem 3-jährigen DFG Stipendium setzte Dr. Herling im Jahr 2007 seine Arbeiten an der Klinik für Innere Medizin I der Universität Köln fort. Hier gründete er sein wissenschaftliches Labor für lymphozytäres Signaling und Onkoproteom. Von 2008 - 2015 war dies auch Kern seiner Max-Eder-Nachwuchsgruppe der Deutschen Krebshilfe  zu Aspekten der Kinaseregulation im Mikromilieusignaling der CLL. Er ist Principal Investigator im CECAD und ZMMK.

Von 2006 - 2010 leitete Dr. Herling die Befundung im diagnostischen Zellmarkerlabor. Als Facharzt für Innere Medizin und Hämatologie / Onkologie leitet Dr. Herling das wissenschaftliche und klinische Programm zu T-Zell Leukämien, insbesondere zur T-PLL und der T-LGL (z.B. Zweitmeinungssprechstunde, Register, etc; weiterführende Informationen). Von ihm initiierte und geleitete Forschungsverbünde sind die DFG FOR1961 “CONTROL-T”  (Consortium for TCR-mediated Regulation and Oncogenesis in Lymphomas of T-cells), sowie die EU Netzwerke Transcan-2 “Implementation of (epi)genetic and metabolic networks in the targeting of T-PLL” (2019) und ERAPerMed “Novel individualized therapies in JAK/STAT-driven T-cell malignancies” (2019).

Seit 2010 ist Dr. Herling Adjunct Assistant Professor am Department of Hematopathology des MDACC. Er ist seit 2019 Oberarzt der Klinik I für Innere Medizin.

Dr. Herling ist aktives Mitglied der American Society of Hematology, American Society of Oncology, American Association for Cancer Research, der Deutschen Gesellschaft für Hämatologie und Onkologie, der GLA (AG T-Zell Lymphome) und anderer Fachgesellschaften. Er ist ad hoc Gutachter zahlreicher internationaler und nationaler Fachzeitschriften und Förderorganisationen. Nationale Leitlinien unter seiner federführenden Autorenschaft sind u.a. „Stellenwert der Richter Transformation“ in der S3 Leitlinie „CLL“, sowie „T-Zell Prolymphozytenleukämie“ im DGHO Portal ‚Onkopedia‘.

Klinische Schwerpunkte

  • Lymphome und Leukämien
  • Molekulare Tumordiagnostik
  • Diagnose, prognostische Einstufung und Therapieoptimierung in T-Zell Neoplasien
  • Zelluläre Therapien, insbesondere allogene Stammzelltransplantation
  • Virusinfektionen im Kontext von Immunsuppression

Zusatzqualifikationen

  • DAG-KBT Zertifikat „Leitung eines allogenen Stammzellprogramms“
  • DEGUM Zertifikate I-III Ultraschall „Innere Medizin / Abdomen“

Wissenschaftliche Schwerpunkte

  • Biologie der Lymphome und lymphozytären Leukämien
  • Onkogener, Redox- und genotoxischer Stress des alternden / malignen Lymphozyten
  • Antigen-rezeptor Signaling und Kinom in T-Zell und B-Zell Lymphomen
  • Determinanten klonaler Homöostase in prä-lymphomatösen Läsionen (Modelle)
  • Ancestrale Beziehung von T-Zell Tumoren mit der myeloischen Hämatopoese
  • Interventionelle Modulation spezifischer Tumorimmunmikromilieus
  • Molekulare Vulnerabilitäten und neue therapeutische Synergismen

10 wichtigste Publikationen

  • Schrader A, Crispatzu G, Oberbeck S, Mayer P, Pützer S, von Jan J, Vasyutina E, Warner K, Weit N, Pflug N, Braun T, Andersson EI, Yadav B, Riabinska A, Maurer B, Ventura Ferreira MS, Beier F, Altmüller J, Lanasa M, Herling CD, Haferlach T, Stilgenbauer S, Hopfinger G, Peifer M, Brümmendorf TH, Nürnberg P, Elenitoba-Johnson KSJ, Zha S, Hallek M, Moriggl R, Reinhardt HC, Stern MH, Mustjoki S, Newrzela S, Frommolt P, Herling M. Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun 2018 Feb 15;9(1):697; IF 2017/18: 12.353

  • Lohmann G, Vasyutina E, Bloehdorn J, Reinart N, Schneider J, Babu V, Knittel G, Crispatzu G, Mayer P, Prinz C‎, Biersack B, Efremov D, Chessa L, Herling CD, Stilgenbauer S, Hallek M, Schobert R, Reinhardt HC, Schumacher B‎, Herling M. Targeting transcription-coupled nucleotide excision repair overcomes resistance in chronic lymphocytic leukemia. Leukemia 2017 May; 31(5):1177-86; IF 2017/18: 10.023

  • Spinner S, Crispatzu G, Yi JH, Munkhbaatar E, Mayer P, Höckendorf U, Müller N, Li Z, Schader T, Bendz H, Hartmann S, Yabal M, Pechloff K, Heikenwalder M, Kelly GL, Strasser A, Peschel C, Hansmann ML, Ruland J, Keller U, Newrzela S, Herling M*, Jost PJ*. Re-activation of mitochondrial apoptosis inhibits T cell lymphoma survival and treatment resistance. Leukemia 2016 Jul;30(7):1520-30. (* shared senior authorship, order as published); IF 2017/18: 10.023          

  • Vasyutina E, Boucas JM, Bloehdorn J, Aszyk C, Crispatzu G, Stiefelhagen M, Breuer A, Mayer P, Lengerke C, Döhner H, Beutner D, Rosenwald A, Stilgenbauer S, Hallek M, Benner A, Herling M. The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL. Leukemia 2015 Oct;29(10):2003-14; IF 2017/18: 10.023

  • Fedorchenko O, Stiefelhagen M, Peer Zada AA, Barthel R, Mayer P, Eckei L, Breuer A, Crispatzu G, Rosen N, Landwehr T, Lilienthal N, Möllmann M, Montesinos-Rongen M, Heukamp L, Dürig J, Hallek M, Fingerle-Rowson G*, Herling M*. CD44 regulates the apoptotic response and promotes disease development in chronic lymphocytic leukemia. Blood 2013 May 16;121(20):4126-36 (* shared senior authorship, order as published); IF 2017/18: 15.132

  • Herling M, Patel KA, Weit N, Lilienthal N, Hallek M, Keating MJ, Jones D. High TCL1 levels are a marker of B-cell receptor pathway responsiveness and therapy resistance in chronic lymphocytic leukemia. Blood 2009 Nov 19;114(21):4675-86; IF 2017/18: 15.132

  • Herling M, Patel KA, Teitell MA, Konopleva M, Ravandi F, Kobayashi R, Jones D. High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia. Blood 2008 Jan 1;111(1):328-37; IF 2017/18: 15.132

  • Herling M, Patel KA, Khalili J, Schlette E, Kobayashi R, Medeiros LJ, Jones D. TCL1 shows a regulated expression pattern in chronic lymphocytic leukemia that correlates with molecular subtypes and proliferative state. Leukemia 2006 Feb;20(2):280-5; IF 2017/18: 10.023

  • Herling M, Khoury JD, Washington LT, Duvic M, Keating MJ, Jones D. A systematic approach to diagnosis of mature T-cell leukemias reveals heterogeneity among WHO categories. Blood 2004 Jul 15;104(2):328-35; IF 2017/18: 15.132

  • Herling M, Teitell MA, Shen RR, Medeiros LJ, Jones D. TCL1 expression in plasmacytoid dendritic cells (DC2) and the related CD4+CD56+ blastic tumors of skin. Blood 2003 Jun 15;101(12):5007-9; IF 2017/18: 15.132 

Scientific Focus

Our laboratory focuses on targetable molecular events of malignant lymphocyte transformation and evaluation of such pathway dependence, with particular interest in the pathogenetic mechanisms of chronic lymphoid leukemias. These comprise a heterogeneous group of tumors derived from mature (peripheral) lymphocytes of B-cell or T-cell lineage, but share a common fact, namely their near-exclusive incurability with current therapeutic approaches. B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia of adults in the Western world with distinct molecular and clinical subsets being recognized. T-cell prolymphocytic leukemia (T-PLL) can be considered its aggressive T-cell equivalent. It shows a unique molecular signature of activation of the T-cell leukemia 1 (TCL1) oncogene. The exact position of T-PLL in the T-cell histogenetic spectrum also deserves further investigation. Mycosis fungoides / Sezary syndrome (MF/SS), another group of CD4+ T-helper cell derived tumors, present as erythematous cutaneous lymphomas / leukemias. They show interesting phenomena of immunophenotypic and functional drift.

Our research program is closely connected to the clinical trial efforts of the German CLL Study Group (GCLLSG) with headquarters at Cologne University as a translational platform. This is of particular significance in an era of multiple available target-specific inhibitors, whose mechanistic rationale can be tested in the laboratory and transferred into bedsite application in collaboration with corporate partners.
In previous work (MDACC Department of Hematopathology, Lab D. Jones, MD, PhD), we studied the regulation and function of a protooncogene called TCL1. Its abnormal activation leads to chronic leukemias and it has been implicated as a major transforming force in T-PLL and CLL. However, its molecular function is still poorly understood. We were able to establish a novel mechanism of TCL1 action by demonstrating its regulatory involvement in cellular signaling processes that represent major survival and growth pathways in transformed lympocytes.

Specific Research Program

Conceptionally, our projects comprise the analysis of relevant kinase signaling and the involvement of novel coregulatory molecules as well as the interception in respective mechanisms of regulatory protein interplay in subtypes of chronic lymphoid leukemias.

  1. temporo-spatial kinetics of TCL1 - protein interactions in B-cell receptor and other micromilieu derived signaling in B-CLL
  2. mechanisms of TCL1 gene regulation and protein turnover
  3. differential kinase activity and regulation in clinical and molecular subsets of B-CLL
  4. stage-dependent changes of proteome patterns / kinome profiles in the oncogenesis of mature T-cell leukemias (T-PLL, MF/SS, T-LGL)
Sources of Funding
Major Collaborations

Hinrich Abken: CAR-T cells as TCR signaling tools

Björn Schumacher: Transcription-coupled nucleotide excision repair

Rainer Siebert: Epigenetic aberrancies in T-PLL

Ingo Röder: Systems biology and modeling of T-cell oncogenesis

Richard Moriggl: JAK/STAT in T-cell neoplasms

Satu Mustjoki: Drug response and synergy screens

Monika Brüggemann: TCR profiling in T-cell leukemias

Marc-Henri Stern: ATM and ROS signaling

Dimitrios Mougiakakos: Metabolic rewiring of malignant T-cells

The Team

Till Braun, cand. med.
Sabine Dondorf, Pharmazeutin
Francien Grotenhuijs, B.Sc.
Jana von Jan, Pharmazeutin
Qu Jiang, M.Sc.
Dennis Jungherz, B.Sc.
Petra Mayer, lab manager
Sebastian Oberbeck, M.Sc.
Alexandra Schrader, PhD
Johanna Stachelscheid, M.Sc
Elena Vasyutina, PhD
Linus Wahnschaffe, cand. med.
Deyu Zou, M.Sc.

Nach oben scrollen