Abstract
Deprivation of T-cell progenitors promotes T-ALL development from thymus-resident progenitor cells.
Major finding: Deprivation of T-cell progenitors promotes T-ALL development from thymus-resident progenitor cells.
Concept: Thymus-resident progenitors self-renew and transform without competition from bone marrow–derived cells.
Impact: Cell competition can prevent tumorigenesis by promoting cell turnover before transformation can occur.
Cell competition, a process in which a weak or harmful cell population is eliminated due to the presence of more fit cells, has been observed in certain contexts but is poorly understood. The thymus, which has an integral role in the development of circulating lymphocytes, depends on continuous migration of T-cell progenitors from the bone marrow but can sustain T-cell development for several months in the absence of its normal source of T-cell progenitors. Martins and colleagues found that prolonged progenitor deprivation and thymic autonomy led to the development of T-cell acute lymphoblastic leukemia (T-ALL). However, T-ALL did not develop in mouse models in which bone marrow progenitors normally populated thymi, suggesting that cell competition regulates normal thymocyte turnover and that disruption of this process leads to oncogenic transformation. In the absence of competition from bone marrow-derived progenitors, thymus-resident progenitors acquired the ability to self-renew and became genomically unstable, acquiring genetic alterations similar to those observed in human T-ALL, such as Notch1 mutations. Moreover, progenitor deprivation initiated some changes in gene expression in the thymus that were maintained in fully malignant T-ALL, as well as other T-ALL–specific changes such as upregulation of the T-ALL oncogenes Lmo2 and Tal1. In the absence of normal cell competition from “young” bone marrow–derived progenitor cells, “old” thymus-resident progenitors also upregulated genes like Hmga1, which is overexpressed in stem cells and human T-ALL, but in the presence of these genetically identical “young” competitors, thymus-resident progenitors underwent specific gene expression changes such as downregulation of the antiapoptotic gene Bcl2, which was associated with increased apoptosis. Together, these findings implicate cell competition in preventing abnormal accumulation and transformation of progenitor cells in the thymus and raise the possibility that cell competition may be a tumor-suppressive mechanism in other tissues with reservoirs of stem and progenitor cells.
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