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EMBO J. 2018 Jul 13;37(14). pii: e98783. doi: 10.15252/embj.201798783. Epub 2018 Jun 7.

Lmo2 expression defines tumor cell identity during T-cell leukemogenesis.

Author information

1
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain.
2
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
3
Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany.
4
Institute of Medical Informatics, University of Muenster, Muenster, Germany.
5
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
6
Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
7
Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria.
8
Department of Pediatric Hematology and Oncology, Justus-Liebig-University Giessen, Giessen, Germany.
9
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
10
Department of Pediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
11
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
12
Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
13
Transgenesis Facility CNB-CBMSO, CSIC-UAM, Madrid, Spain.
14
Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
15
Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
16
Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain.
17
Departamento de Fisiología y Farmacología, Edificio Departamental, Universidad de Salamanca, Salamanca, Spain.
18
Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
19
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain cvd@usal.es Arndt.Borkhardt@med.uni-duesseldorf.de Julia.Hauer@med.uni-duesseldorf.de isg@usal.es.
20
Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany cvd@usal.es Arndt.Borkhardt@med.uni-duesseldorf.de Julia.Hauer@med.uni-duesseldorf.de isg@usal.es.
21
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-USAL, Salamanca, Spain cvd@usal.es Arndt.Borkhardt@med.uni-duesseldorf.de Julia.Hauer@med.uni-duesseldorf.de isg@usal.es.

Abstract

The impact of LMO2 expression on cell lineage decisions during T-cell leukemogenesis remains largely elusive. Using genetic lineage tracing, we have explored the potential of LMO2 in dictating a T-cell malignant phenotype. We first initiated LMO2 expression in hematopoietic stem/progenitor cells and maintained its expression in all hematopoietic cells. These mice develop exclusively aggressive human-like T-ALL In order to uncover a potential exclusive reprogramming effect of LMO2 in murine hematopoietic stem/progenitor cells, we next showed that transient LMO2 expression is sufficient for oncogenic function and induction of T-ALL The resulting T-ALLs lacked LMO2 and its target-gene expression, and histologically, transcriptionally, and genetically similar to human LMO2-driven T-ALL We next found that during T-ALL development, secondary genomic alterations take place within the thymus. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated. Restricted Cre-mediated activation of Lmo2 at different stages of B-cell development induces systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. Together, these results provide a novel paradigm for the generation of tumor T cells through reprogramming in vivo and could be relevant to improve the response of T-ALL to current therapies.

KEYWORDS:

cancer initiation; epigenetic priming; mouse models; oncogenes; stem cells

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