Laboratory of Lymphocyte Signaling and Oncoproteome

(Max-Eder-Nachwuchsgruppe der Deutschen Krebshilfe)

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.

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Kurzbiografie

Dr. 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 unter Prof’s A.H. Sarris und L.J. Medeiros am M. D. Anderson Cancer Center (MDACC) Department of Lymphoma and Myeloma an der Etablierung prognostischer Markermodelle zum großzellig anaplastischen T-Zell Lymphom und dem Hodgkin Lymphom. Seine Arbeiten zur Promotion zum Dr. med. am Pathologischen Institut der MLU (Direktor Prof. em. F.W. Rath) zwischen 1994-1999 beschrieben präsarkomatöse Veränderungen sowie Tumor-Wirt Interaktionen im chronologischen Längsschnitt experimentell induzierter mesenchymaler Tumoren 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 unter Leitung von Prof. R. Mertelsmann. Im Jahre 2002 begann Dr. Herling sein Postdoctoral Fellowship im Labor von Prof. D. Jones im MDACC Department of Hematopathology zu pathogenetischen Mechanismen in T-Zell Neoplasien mit Fokus auf die Rolle des Onkogens TCL1. Als Absolvent des NIH Physician Scientist Training Program unter klinischem Mentor Prof. E.J. Freireich zwischen 2002-2005 konnte Dr. Herling Aspekte seiner laborexperimentellen Arbeiten in neuen klinischen Studiendesigns (adaptierte Randomisierung, Bayesian statistics) zu chronischen lymphozytären Leukämien (T-PLL) übertragen. Als Träger des MDACC Odyssey Special Fellow Award von 2004-2006 erweiterte Dr. Herling seine Untersuchungen zu Antigenrezeptor vermittelten Mechanismen der Transformation und Tumorprogression auf B-Zell Neoplasien, insbesondere die B-CLL.

Mit einem DFG Stipendium setzte Dr. Herling im Jahre 2006 seine Arbeiten an der Klinik für Innere Medizin I der Universität Köln unter Leitung von Prof. M. Hallek fort. Hier leitet er seit 2007 eine Max-Eder-Nachwuchsgruppe der Deutschen Krebshilfe zu Aspekten der Kinaseregulation im Mikromilieusignaling der B-CLL. Von 2006 - 2010 leitete Dr. Herling die Befundung im diagnostischen Zellmarkerlabor.

Seit 2010 ist Dr. Herling Adjunct Assistant Professor am Department of Hematopathology des MDACC.

Dr. Herling ist aktives Mitglied der American Society of Hematology, American Society of Oncology, der Deutschen Gesellschaft für Hämatologie und Onkologie sowie des Steering Committee der MDACC Faculty and Alumni Association.

Forschungsschwerpunkte

  • Bedeutung und Regulation der Antigenrezeptor Signalübertragung in der lymphatischen Onkogenese
  • Spezifische Inhibition in onkogenetisch relevanten Protein-Kinase Interaktione
  • Das Tumormikromilieu in der Evolution reifer B- und T-Zell Lymphome
  • Histogenetische, funktionelle und Target-orientierte Klassifikation lymphozytärer Neoplasien

Klinische Schwerpunkte

  • Therapieoptimierung in reifen T-Zellneoplasien
  • Diagnostik, prognostische Einstufung und Behandlung lymphatischer Tumoren
  • Neue Ansätze im klinischen Studiendesign in der translationalen Hämatoonkologie
  • Evidenz basierte Supportivtherapie

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

H. Abken, MD, CMMC (CAR's and TCR signaling)

J. Burger, MD, PhD, Dept. of Leukemia, MDACC, Houston, TX (chemokine mediated microenvironmental signaling and its interception in CLL)

J. Dürig, MD, Essen University (inihibition of CLL-micromilieu interaction in the SCID mouse xenograft model)

G. Fingerle-Rowson, MD, PhD, Dept. of Medicine I, Cologne University (animal models for in cancer target validation, GCLLSG)

P. Frommolt, PhD, CECAD Bioinformatics Core (integrative analytic approaches to high-throughput data in lymphatic leukemias)

J. Hescheler, MD / T. Saric, MD, PhD / A. Sachinidis, MD, Cologne University, Institute of Neurophysiology (the role of oncogenes in embryonic stem cells)

S. Newrzela, PhD, Goethe University Frankfurt/M, Senckenberg Institute of Pathology (Perturbation of T-cell homeostasis)

A. Rosenwald, Dept. of Pathology, University of Würzburg (TCL1 in B-cell lymphoma)

B. Schumacher, PhD, Cologne University, Institute of Genetics / CECAD (TCL1 and DNA damage in the context of lymphocyte ageing)

M. Trepel, MD, University of Hamburg (the B-cell receptor in the biology of CLL)

The Team

Lab Coordination/Technical Assistance
Petra Mayer, MTLA

Postdoctoral Fellows
Elena Vasyutina, PhD, CV
Alexandra Schrader, PhD, CV

Ph.D. Students
Christoph Aszyk, M.Sc.
Giuliano Crispatzu, M.Sc.
Sabine Dondorf, Pharmacist
Sebastian Oberbeck, M.Sc.
Christian Prinz, Pharm-D
Kathrin Warner, M.Sc.

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