FoxN1-dependent thymic epithelial cells promote T-cell leukemia development

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. The role of thymic microenvironmental cells and stromal factors in thymocyte malignant transformation and T-ALL development remains little explored. Here, using the TEL-JAK2 transgenic (TJ2-Tg) mouse model of T-ALL, which is driven by constitutive JAK/STAT signaling and characterized by the acquisition of Notch1 mutations, we sought to identify stromal cell alterations associated with thymic leukemogenesis. Immunofluorescence analyses showed that thymic lymphomas presented epithelial areas characterized by keratin 5 and keratin 8 expression, adjacently to keratin-negative, epithelial-free areas. Both keratin-positive and -negative areas stained conspicuously with ER-TR7 (a fibroblast marker), laminin, and CD31 (an endothelial cell marker). Besides keratin 5, keratin-positive areas were also labeled by the Ulex Europaeus agglutinin-1 medullary thymic epithelial cell (TEC) marker. To assess whether TECs are important for T-ALL development, we generated TJ2-Tg mice heterozygous for the FoxN1 transcription factor nude null mutation. In contrast to nude homozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;Foxn1+/nu compound mice both emergence of malignant cells in pre-leukemic thymi and overt T-ALL onset were significantly delayed. Moreover, in transplantation assays leukemic cell expansion in the thymus of recipient Foxn1+/nu mice was reduced as compared to control littermates. These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development.\n\nSummaryIn a mouse model of T-ALL, several cellular alterations were detected in thymic lymphomas, including altered epithelial distribution and increased proportion of fibroblasts or endothelial cells. Reduced dosage of FoxN1, a thymic epithelial transcription factor, delayed leukemogenesis in these mice.