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

MN Ghezzo; MT Fernandes; RS Machado; I Pacheco-Leyva; MAS Araújo; RK Kalathur; ME Futschik; NL Alves; Santos NR dos

doi:10.1101/247015

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

MN Ghezzo, MT Fernandes, RS Machado, I Pacheco-Leyva, MAS Araújo, RK Kalathur, ME Futschik, NL Alves, Santos NR dos

School of Biomedical Sciences

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Abstract

AbstractT-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 ofNotch1mutations, 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 theUlex Europaeusagglutinin-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 factornudenull mutation. In contrast tonudehomozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;Foxn1+/nucompound 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 recipientFoxn1+/numice was reduced as compared to control littermates. These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development.SummaryIn 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.

Original language	English
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DOIs	https://doi.org/10.1101/247015
Publication status	Published - 11 Jan 2018

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10.1101/247015

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FoxN1-dependent thymic epithelial cells promote T-cell leukemia development
Ghezzo, M. N., Fernandes, M. T., Pacheco-Leyva, I., Rodrigues, P. M., Machado, R. S., Araujo, M., Kalathur, R. K., Futschik, M. E., Alves, N. L. & dos, S. N., Dec 2018, In: Carcinogenesis. 39, 12, p. 1463-1476
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title = "FoxN1-dependent thymic epithelial cells promote T-cell leukemia development",

abstract = "AbstractT-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 ofNotch1mutations, 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 theUlex Europaeusagglutinin-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 factornudenull mutation. In contrast tonudehomozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;Foxn1+/nucompound 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 recipientFoxn1+/numice was reduced as compared to control littermates. These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development.SummaryIn 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.",

author = "MN Ghezzo and MT Fernandes and RS Machado and I Pacheco-Leyva and MAS Ara{\'u}jo and RK Kalathur and ME Futschik and NL Alves and dos, \{Santos NR\}",

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AU - Ghezzo, MN

AU - Fernandes, MT

AU - Machado, RS

AU - Pacheco-Leyva, I

AU - Araújo, MAS

AU - Kalathur, RK

AU - Futschik, ME

AU - Alves, NL

AU - dos, Santos NR

PY - 2018/1/11

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N2 - AbstractT-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 ofNotch1mutations, 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 theUlex Europaeusagglutinin-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 factornudenull mutation. In contrast tonudehomozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;Foxn1+/nucompound 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 recipientFoxn1+/numice was reduced as compared to control littermates. These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development.SummaryIn 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.

AB - AbstractT-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 ofNotch1mutations, 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 theUlex Europaeusagglutinin-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 factornudenull mutation. In contrast tonudehomozygous mice, which lack thymus and thymocytes, heterozygous mutant mice present only mild thymocyte maturation defects. In TJ2-Tg;Foxn1+/nucompound 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 recipientFoxn1+/numice was reduced as compared to control littermates. These results indicate that FoxN1 insufficiency impairs specifically thymic leukemogenesis but not thymocyte development.SummaryIn 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.

U2 - 10.1101/247015

DO - 10.1101/247015

M3 - Preprint

VL - 0

T3 - Default journal

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

ER -

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

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

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