Lymphocyte Development and Leukemogenesis

Research in the Lymphocyte development and Leukemogenesis lab focuses on normal T lymphocyte development and on how lymphocyte malignancies can arise from T lymphocyte precursors. Most T lymphocyte development takes place in the thymus from progenitors of bone marrow origin. This is characterized by high cellular turnover, and we found that thymus turnover is regulated by cell competition. In mammals, cell competition is mostly unexplored. In Drosophila, however, cell competition is well studied and considered to be a general homeostatic mechanism that ensures optimal organ function. Specifically, it considers that cellular heterogeneity can occur in tissues (for eg. as result of deleterious mutations) and that this can translate into differences of relative fitness between the cells. The cells can then sense the differences and the more fit – the winners - induce the elimination of the less fit cells – the losers. Therefore, only winner cells will exclusively contribute for the composition of the tissue. We found that an identical mechanism is responsible for regulation of thymus turnover in mice. Specifically, we found that under normal conditions, ‘young’ hematopoietic precursors (that recently seeded the thymus) were more fit than the ‘old’ precursors (residing for longer in the thymus). The presence of the young, led to the elimination of the old precursors, ensuring thymus turnover. Importantly, cell competition is not cell autonomous, i.e., loser cells are viable and, if no winner cells are present, can contribute for the tissue themselves. Likewise, if cell competition in the thymus was impaired, old precursors persisted in the thymus, self-renewed, and for some time gave rise to T lymphocytes. In other words, autonomously maintained thymus function. Nevertheless, while apparently beneficial for a short period, prolonged thymus autonomy led to aggressive T cell acute lymphoblastic leukemia with strong similarities with the human disease. The Lymphocyte development and Leukemogenesis laboratory focuses on the identification of the cellular and molecular mechanisms governing cell competition in normal thymus turnover, and on the changes associated with the malignant transformation of T lymphocyte precursors as a consequence of impaired cell competition.