The Consortium for TCR-mediated Regulation and Oncogenesis in Lymphomas of T-cells (Control-T) is a DFG-funded association of five institutes located in Germany (Speaker: Prof. Martin-Leo Hansmann) with the aim to unravel mechanisms of T-cell lymphoma pathogenesis. Combining the individual expertise of each Control-T member, namely Pathology, Genetics, Hematology, Immunology and Bioinformatics, to focus on a single research area shall lead to novel insight into the pathobiology of this rare and so far less understood entity. The consortium is composed of 6 research projects, 5 are currently active.
In the second funding period, starting January 2017, we aim to build on the successful implementation of our consortium and the first reassuring results, which support our original model. Our goal is to uncover key mechanisms of MTCL pathogenesis and
clarify the interplay between oncogenic events and the impact of homeostatic regulation and dysregulation in this process. The group has been strengthend by inclusion of a new project focused on the role of microenvironmental interactions in the pathogenesis of anaplastic large cell lymphoma (RP7, S. Hartmann). Beyond the area of T-cell lymphoma biology, the results generated here will likely have a major impact on the basic understanding of lymphomagenesis and on T-cell immunology in gen-
The research projects (RP)
RP1: Pathogenesis of angioimmunoblastic T-cell lymphoma
The Cancer Research Laboratory within the Institute of Cell Biology at University of Duisburg-Essen (PI: Prof. Ralf Küppers) applies next generation sequencing (NGS) on cases of angioimmunoblastic T-cell lymphoma (AITL) to identify novel driver mutations. As a next step, candidate genes can be validated in a mouse model (see RP2) and other lymphoid neoplasm will be assessed for the identified mutations. Moreover, the B-cell compartment in AITL shall be investigated likewise, as monoclonal B-cell proliferations are often observed.
RP2: Homeostatic niches - control mechanisms in mature T-cell leukemia/lymphoma (2013-2016)
Located in the Dr. Senckenberg Institute of Pathology at Goethe-University of Frankfurt, the Lymphoma Group (PI: Dr. Sebastian Newrzela and Dr. Benjamin Rengstl) developed a mouse model for anaplastic large cell lymphoma (ALCL) to investigate the influence of homeostatic population dynamics on lymphomagenesis. In addition, this model system is well suited to test putative driver mutations as well as novel candidate genes for their oncogenic potential (see RP1). Furthermore, molecular pathways are investigated with respect to clonal outgrowth. Although RP2 is no longer active, the findings during the first funding period are an indispensable fundament for the second funding period.
RP 3: Mechanisms of T-cell homeostasis and its perturbation in lymphomagenesis:
As part of the Dep. of Immunology at the Federal Institute for Vaccines and Biomedicines (Paul-Ehrlich-Institut) the group of Dr. Jörg Kirberg is working on T-cell homeostasis with the aim to identify factors facilitating T-cell distribution in vivo. Influencing the circulation of T cells uncloses data points necessary to formulate a mathematical model (see RP4) and is the first step in understanding distribution of neoplastic T cells.
RP 4: Mathematical modeling of homeostasis and oncogenesis in mature T cells:
The Group of Dr. Ingo Röder from the Institute for Medical Informatics and Biometry at University of Dresden plays a central role in the consortium. On one hand so called big data, i.e. collected by NGS (see RP1), is analyzed via the bioinformatics pipeline and on the other hand mathematical models for T-cell homeostasis as well as its perturbation under neoplastic conditions are generated (see RP2 and RP3).
RP 5: Mechanisms of the oncogenic cooperation of TCL1 with T-cell receptor signaling in T-PLL:
At University of Cologne two associated groups from the Dep. I of Internal Medicine (PI: Dr. Marco Herling) and the Center for Molecular Medicine (PI: Prof. Hinrich Abken) are combining their expertise to unravel the impact of T-cell receptor signaling on the pathogenesis of T-cell lymphomas with the main focus on T-cell prolymphocytic leukemia (T-PLL). Next to analysis of patient material and genetic engineering of T-cells, TCL1 as main oncogene of T-PLL is investigated using the afore mentioned mouse model (see RP2).
RP 7: The role of chemokine ligands and receptors in the dissemination of anaplastic large cell lymphoma (joined in the second funding period)
RP 7 joined the Control-T consortium in the second funding period and is headed by Prof. Dr. Sylvia Hartmann. RP7 brings into the consortium a second main human MTCL, namely ALCL, and brings also the lymphoma microenvironment into focus of our program.
Beyond the area of T-cell lymphoma biology, the results generated here will likely have a major impact on the basic understanding of lymphomagenesis and on T-cell immunology in general.