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

被引:6
|
作者
Carr, Tiffany [1 ]
McGregor, Stephanie [2 ,8 ]
Dias, Sheila [3 ]
Verykokakis, Mihalis [3 ,9 ]
Le Beau, Michelle M. [4 ]
Xue, Hai-Hui [5 ]
Sigvardsson, Mikael [6 ]
Bartom, Elizabeth T. [7 ]
Kee, Barbara L. [1 ,2 ,3 ]
机构
[1] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA
[2] Univ Chicago, Comm Canc Biol, Chicago, IL 60637 USA
[3] Univ Chicago, Dept Pathol, 5841 S Maryland Ave, Chicago, IL 60637 USA
[4] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA
[5] Hackensack Univ, Ctr Discovery & Innovat, Med Ctr, Nutley, NJ USA
[6] Lund Univ, Dept Mol Hematol, Lund, Sweden
[7] Northwestern Univ, Dept Biochem & Mol Genet, Chicago, IL 60611 USA
[8] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USA
[9] Biomed Sci Res Ctr BSRC Aexander Fleming, Vari, Greece
来源
FRONTIERS IN IMMUNOLOGY | 2022年 / 13卷
关键词
E2a; Lef1; leukemia; thymus; lymphocyte; CELL DEVELOPMENT; TRANSCRIPTION FACTORS; TAL1; COMPLEX; E-PROTEINS; C-MYC; NOTCH1; ACTIVATION; EXPRESSION; RECEPTOR; ROLES;
D O I
10.3389/fimmu.2022.845488
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
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页数:13
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