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Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia

T lymphocyte acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease affecting T cells at multiple stages of their development and is characterized by frequent genomic alterations. The transcription factor LEF1 is inactivated through mutation in a subset of T-ALL cases but elevated LEF1 expr...

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Autores principales: Carr, Tiffany, McGregor, Stephanie, Dias, Sheila, Verykokakis, Mihalis, Le Beau, Michelle M., Xue, Hai-Hui, Sigvardsson, Mikael, Bartom, Elizabeth T., Kee, Barbara L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971981/
https://www.ncbi.nlm.nih.gov/pubmed/35371057
http://dx.doi.org/10.3389/fimmu.2022.845488
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author Carr, Tiffany
McGregor, Stephanie
Dias, Sheila
Verykokakis, Mihalis
Le Beau, Michelle M.
Xue, Hai-Hui
Sigvardsson, Mikael
Bartom, Elizabeth T.
Kee, Barbara L.
author_facet Carr, Tiffany
McGregor, Stephanie
Dias, Sheila
Verykokakis, Mihalis
Le Beau, Michelle M.
Xue, Hai-Hui
Sigvardsson, Mikael
Bartom, Elizabeth T.
Kee, Barbara L.
author_sort Carr, Tiffany
collection PubMed
description T lymphocyte acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease affecting T cells at multiple stages of their development and is characterized by frequent genomic alterations. The transcription factor LEF1 is inactivated through mutation in a subset of T-ALL cases but elevated LEF1 expression and activating mutations have also been identified in this disease. Here we show, in a murine model of T-ALL arising due to E2a inactivation, that the developmental timing of Lef1 mutation impacts its ability to function as a cooperative tumor suppressor or oncogene. T cell transformation in the presence of LEF1 allows leukemic cells to become addicted to its presence. In contrast, deletion prior to transformation both accelerates leukemogenesis and results in leukemic cells with altered expression of genes controlling receptor-signaling pathways. Our data demonstrate that the developmental timing of Lef1 mutations impact its apparent oncogenic or tumor suppressive characteristics and demonstrate the utility of mouse models for understanding the cooperation and consequence of mutational order in leukemogenesis.
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spelling pubmed-89719812022-04-02 Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia Carr, Tiffany McGregor, Stephanie Dias, Sheila Verykokakis, Mihalis Le Beau, Michelle M. Xue, Hai-Hui Sigvardsson, Mikael Bartom, Elizabeth T. Kee, Barbara L. Front Immunol Immunology T lymphocyte acute lymphoblastic leukemia (T-ALL) is a heterogeneous disease affecting T cells at multiple stages of their development and is characterized by frequent genomic alterations. The transcription factor LEF1 is inactivated through mutation in a subset of T-ALL cases but elevated LEF1 expression and activating mutations have also been identified in this disease. Here we show, in a murine model of T-ALL arising due to E2a inactivation, that the developmental timing of Lef1 mutation impacts its ability to function as a cooperative tumor suppressor or oncogene. T cell transformation in the presence of LEF1 allows leukemic cells to become addicted to its presence. In contrast, deletion prior to transformation both accelerates leukemogenesis and results in leukemic cells with altered expression of genes controlling receptor-signaling pathways. Our data demonstrate that the developmental timing of Lef1 mutations impact its apparent oncogenic or tumor suppressive characteristics and demonstrate the utility of mouse models for understanding the cooperation and consequence of mutational order in leukemogenesis. Frontiers Media S.A. 2022-03-18 /pmc/articles/PMC8971981/ /pubmed/35371057 http://dx.doi.org/10.3389/fimmu.2022.845488 Text en Copyright © 2022 Carr, McGregor, Dias, Verykokakis, Le Beau, Xue, Sigvardsson, Bartom and Kee https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Carr, Tiffany
McGregor, Stephanie
Dias, Sheila
Verykokakis, Mihalis
Le Beau, Michelle M.
Xue, Hai-Hui
Sigvardsson, Mikael
Bartom, Elizabeth T.
Kee, Barbara L.
Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia
title Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia
title_full Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia
title_fullStr Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia
title_full_unstemmed Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia
title_short Oncogenic and Tumor Suppressor Functions for Lymphoid Enhancer Factor 1 in E2a(-/-) T Acute Lymphoblastic Leukemia
title_sort oncogenic and tumor suppressor functions for lymphoid enhancer factor 1 in e2a(-/-) t acute lymphoblastic leukemia
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971981/
https://www.ncbi.nlm.nih.gov/pubmed/35371057
http://dx.doi.org/10.3389/fimmu.2022.845488
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