Laboratory of Lymphocyte Signaling and Oncoproteome
(Max-Eder-Nachwuchsgruppe der Deutschen Krebshilfe)
CECAD Research Center
50924 Köln (Cologne)
phone +49 221 478-5969 (lab)
phone +49 221 478-5194 (office)
fax +49 221 478-6383
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.
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.
TCL1 expression in normal B-cells, T-PLL, and B-CLL (left to right)
In previous work (Laboratory 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.
- temporo-spatial kinetics of TCL1 - protein interactions in B-cell receptor and other micromilieu derived signaling in B-CLL
- mechanisms of TCL1 gene regulation and protein turnover
- differential kinase activity and regulation in clinical and molecular subsets of B-CLL
- stage-dependent changes of proteome patterns / kinome profiles in the oncogenesis of mature T-cell leukemias (T-PLL, MF/SS, T-LGL)
Lab Coordination/Technical Assistance
Alexandra Breuer, MTLA
Petra Mayer, MTLA
Esther M. Walter
Dr. rer. nat. Nils Lilienthal, PhD 01/2012
Dr. rer. medic. W. Popal, PhD 04/2013
Dr. rer. medic. H. Liu, PhD 10/2013
Dr. rer. medic. N. Weit, PhD 06/2014
no positions available at the moment
Sources of Funding
Deutsche Krebshilfe (Max-Eder-Nachwuchsgruppe)
Deutsche Forschungsgemeinschaft (DFG)
Deutsche José Carreras Leukämie-Stiftung e.V.
Bundesministerium für Bildung und Forschung
CLL Global Research Foundation
Stiftungsverbund of the University of Cologne
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)
Hopfinger G, Weit N, Herling M
Recent developments in the treatment of peripheral T-cell lymphoma.
Magazine of European Medical Oncology 2010;3:73–6
Hopfinger G, Weit N, Herling M.
Diagnostische Schritte und Therapieoptionen bei peripheren T-Zell-Neoplasien.
Wiener Klinische Wochenschrift 2009;4:165-76
Hopfinger G and Herling M.
Mature T-cell malignancies: a diagnostic and therapeutic challenge.
Magazine of European Medical Oncology 2009;2:134-41
Herling M and Jones D.
CD4+CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells.
Am J Clin Pathol 2007 May;127(5):687-700
Herling M and Jones D.
Mature T-cell leukemias - Current challenges in diagnosis and therapy.
Am J Oncol Rev 2004 Oct;3(10):608-17
Clinical Management of non-cutaneous T-cell and NK-cell malignancies.
Chapter 23 (pp.413-26) in: Jones D. ed. Neoplastic Hematopathology - Experimental
and Clinical Approaches, 2010, Springer
Herling M , Daskalakis M, Engelhardt R.
Antiemetische Prophylaxe und Therapie.
In: Berger - Engelhardt - Mertelsmann eds.
Das Rote Buch - Hämatologie und Internistische Onkologie.
2 nd ed. 2002, Ecomed Verlag
Herling M , Hinze R, Knolle J, Bahn H, Gabius HJ,Rath FW.
Glykohistochemische Untersuchungen an Benzpyren-induzierten Sarkomen und deren Frühstadien.
Verh Dtsch Ges Pathol 1998; 82:378-84 (Yearbook of the German Society of Pathology
A look at cancer chemoprevention research - where do we stand?
Am J Hem Oncol 2009 Oct; 8(10):456-8