FOR 1961:  Mature T-Cell Lymphomas - Mechanisms of Perturbed Clonal T-Cell Homeostasis

• Subject Area: Medicine
• Term: from 2013 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 225165194

The major incentive for CONTROL-T is the poor understanding of the pathogenesis of mature T-cell lymphomas/leukemias (MTCL) in light of their mostly detrimental clinical outcome. Beyond conventional, oncogene-based approaches, we conceptualize the firm integration of immunological concepts in this consortium, bringing together immunologists, pathologists, geneticists, oncologists, and mathematicians. Based on prior work, we hypothesized that in addition to genetic lesions, the pathogenesis of MTCL centrally includes a disturbed T-cell homeostasis. This is ascribed to the specific physiology of mature T cells, ruled by clonal competition during homeostatic or antigen-driven expansion and later retraction. A central relay in these processes is the T-cell receptor (TCR), defining clonal competitiveness. To test the hypothesis whether lymphomagenesis is affected by specific oncogenes that drive TCR signaling towards disturbed homeostasis, we integrated three fields of research: 1) The TCR ruling normal T-cell homeostasis, 2) escape from T-cell homeostasis during MTCL development, and 3) impact of T-cell oncogenes on MTCL pathogenesis.In the first funding period intensive collaborations between the partners advanced and we substantiated the proposed concepts and in-vivo models. Importantly, the results validated the usefulness of the overall models. The initial findings have been used to feed mathematical modeling, using its predictions to adapt experimentation.In the second period we want to consolidate and improve our concepts on the interplay between TCR input, the driving oncogene(s), and the interrelation of these with respect to Tcell homeostasis and oncogenesis. Experimental data and modeling efforts will refine our central hypothesis, adding new perspectives, e.g. the importance of local differences in selfpeptide representation for T-cell diversity or shifts in the dependency on TCR or cytokine signaling. New strategies will trace the very early steps in MTCL development and address the role of micromilieu interactions.The added value of the consortium is generated by complementary interdisciplinary expertise and having various MTCL models available. Thus, scientific questions can be approached that none of the applicants would be able to solve alone.Overall, the expected results will improve the general understanding of MTCL pathogenesis and may have an impact with respect to basic T-cell immunology.

• DFG Programme: Research Units

Projects

• Coordinating central project of the Research Unit (Applicant Hansmann, Martin-Leo )
• Coordinating central project of the Research Unit (Applicant Hansmann, Martin-Leo )
• Homeostatic niches-control mechanisms in mature T-cell leukemia/lymphoma (Applicants Hansmann, Martin-Leo ;  Newrzela, Sebastian )
• Mathematical modeling of homeostasis and oncogenesis in mature T-cells (Applicant Röder, Ingo )
• Mechanisms of T-cell homeostasis and its perturbation in lymphomagenesis (Applicant Kirberg, Jörg )
• Pathogenesis of angioimmunoblastic T-cell lymphoma (Applicants Hansmann, Martin-Leo ;  Küppers, Ralf )
• The oncogenic cooperation of TCL1 with T-cell receptor signaling in T-PLL (Applicants Abken, Hinrich ;  Herling, Marco )
• The role of chemokine ligands and receptors in the dissemination of anaplastic large cell lymphoma (Applicant Hartmann, Sylvia )

• Spokesperson: Professor Dr. Martin-Leo Hansmann