{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T12:22:25Z","timestamp":1768479745004,"version":"3.49.0"},"posted":{"date-parts":[[2018,1,11]]},"group-title":"Cancer Biology","reference-count":69,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2018,1,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  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\n                  <jats:italic>Notch1<\/jats:italic>\n                  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\n                  <jats:italic>Ulex Europaeus<\/jats:italic>\n                  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\n                  <jats:italic>nude<\/jats:italic>\n                  null mutation. In contrast to\n                  <jats:italic>nude<\/jats:italic>\n                  homozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;\n                  <jats:italic>Foxn1<\/jats:italic>\n                  <jats:sup>+\/nu<\/jats:sup>\n                  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\n                  <jats:italic>Foxn1<\/jats:italic>\n                  <jats:sup>+\/nu<\/jats:sup>\n                  mice was reduced as compared to control littermates. These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>In 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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/247015","type":"posted-content","created":{"date-parts":[[2018,1,12]],"date-time":"2018-01-12T01:10:34Z","timestamp":1515719434000},"source":"Crossref","is-referenced-by-count":0,"title":["FoxN1-dependent thymic epithelial cells promote T-cell leukemia development"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9197-5318","authenticated-orcid":false,"given":"Marinella N.","family":"Ghezzo","sequence":"first","affiliation":[]},{"given":"M\u00f3nica T.","family":"Fernandes","sequence":"additional","affiliation":[]},{"given":"Rui S.","family":"Machado","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3006-2264","authenticated-orcid":false,"given":"Ivette","family":"Pacheco-Leyva","sequence":"additional","affiliation":[]},{"given":"Marta 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