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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Published inFrontiers in immunology Vol. 13; p. 845488
Main Authors Carr, Tiffany, McGregor, Stephanie, Dias, Sheila, Verykokakis, Mihalis, Le Beau, Michelle M, Xue, Hai-Hui, Sigvardsson, Mikael, Bartom, Elizabeth T, Kee, Barbara L
Format Journal Article
LanguageEnglish
Published Switzerland Frontiers Media S.A 18.03.2022
Subjects
Animals
Cancer and Oncology
Cancer och onkologi
Clinical Medicine
E2a
Immunology
Klinisk medicin
Lef1
leukemia
lymphocyte
Medical and Health Sciences
Medicin och hälsovetenskap
Mice
Oncogenes
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
TCF Transcription Factors - genetics
thymus
Transcription Factors - metabolism
Lef1
leukemia
thymus
E2a
lymphocyte
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Summary: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 inactivation, that the developmental timing of 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 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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Edited by: Takashi MaruYama, National Institutes of Health (NIH), United States
Present address: Stephanie McGregor, Dept. of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, United States; Mihalis Verykokakis, Biomedical Sciences Research Center (BSRC) “Aexander Fleming”, Vari, Greece
Reviewed by: Masaki Miyazaki, Kyoto University, Japan; Phuong Cao Thi Ngoc, Lund University, Sweden
This article was submitted to T Cell Biology, a section of the journal Frontiers in Immunology
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2022.845488