Project Details
Projekt
Homeostatic niches-control mechanisms in mature T-cell leukemia/lymphoma
Subject Area
Pathology
Term
from 2013 to 2016
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 225165194
To assess the capacity of mature T cells to become oncogenetically transformed we overexpressed different T-cell (proto-)oncogenes in mature T cells or hematopoietic stem cells/progenitor cells (HSC/HPC). We found that transduced HSC/HPC readily induced T-cell leukemia/lymphoma in mice. However, mature T-cell receptor (TCR) polyclonal T cells could not be transformed. Quite surprisingly, TCR quasi-monoclonal T lymphocytes (OT-I) were transformed with the same kinetics and efficiency as stem cells. Within an ongoing DFG project (LA1135/9-1) we could transform a further TCR monoclonal T-cell type (P14), indicating that this observation is a general phenomenon. Moreover, we found that addition of polyclonal T-cell populations prevented malignancies and we excluded immunological processes as a controlling factor. As it is described for normal T-cell homeostasis, we hypothesize, that outgrowth of pre-leukemic clones is controlled by the competition of different T-cell clones for stimulatory MHC-self-peptide niches, an underlying hypothesis of several projects within the proposed research unit (CONTROL-T). Our experimental observations clearly demonstrate that outgrowth of peripheral T-cell tumors is prevented by TCR-polyclonality. We plan to analyze the population-dynamics in leukemia/lymphoma development and to elucidate the molecular mechanisms that control the development of T-cell malignancies in the TCR-polyclonal scenario. Furthermore, our experimental system is highly relevant for evaluating the safety of retroviral vector-based T-cell gene therapy.
DFG Programme
Research Units
