Lmo2 expression defines tumor cell identity during T-cell leukemogenesis

Idoia García-Ramírez; Sanil Bhatia; Guillermo Rodríguez-Hernández; Inés González-Herrero; Carolin Walter; Sara González de Tena-Dávila; Salma Parvin; Oskar Haas; Wilhelm Woessmann; Martin Stanulla; Martin Schrappe; Martin Dugas; Yasodha Natkunam; Alberto Orfao; Verónica Domínguez; Belén Pintado; Oscar Blanco; Diego Alonso-López; Javier De Las Rivas; Alberto Martín-Lorenzo; Rafael Jiménez; Francisco Javier García Criado; María Begoña García Cenador; Izidore S Lossos; Carolina Vicente-Dueñas; Arndt Borkhardt; Julia Hauer; Isidro Sánchez-García

doi:10.15252/embj.201798783

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Lmo2 expression defines tumor cell identity during T-cell leukemogenesis

Journal article

Open access

Peer reviewed

Lmo2 expression defines tumor cell identity during T-cell leukemogenesis

Idoia García-Ramírez, Sanil Bhatia, Guillermo Rodríguez-Hernández, Inés González-Herrero, Carolin Walter, Sara González de Tena-Dávila, Salma Parvin, Oskar Haas, Wilhelm Woessmann, Martin Stanulla, …

The EMBO journal, Vol.37(14), p.n/a

2018-07-13

DOI: https://doi.org/10.15252/embj.201798783

PMCID: PMC6043907

PMID: 29880602

Abstract

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology

Animals

Cell Transformation, Neoplastic

Histocytochemistry

Thymus Gland - pathology

Hematopoietic Stem Cells - physiology

Gene Expression Profiling

Mice

Adaptor Proteins, Signal Transducing - metabolism

LIM Domain Proteins - metabolism

Carcinogenesis

Disease Models, Animal

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 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 and could be relevant to improve the response of T-ALL to current therapies.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.103 Blood Disorders; 1.103.155 Acute Myeloid Leukemia
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: Lmo2 expression defines tumor cell identity during T-cell leukemogenesis
Creators: Idoia García-Ramírez - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Sanil Bhatia - Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany
Guillermo Rodríguez-Hernández - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Inés González-Herrero - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Carolin Walter - Institute of Medical Informatics, University of Muenster, Muenster, Germany
Sara González de Tena-Dávila - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Salma Parvin - Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
Oskar Haas - Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria
Wilhelm Woessmann - Department of Pediatric Hematology and Oncology, Justus-Liebig-University Giessen, Giessen, Germany
Martin Stanulla - Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Martin Schrappe - Department of Pediatrics, Christian-Albrechts-University of Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany
Martin Dugas - Institute of Medical Informatics, University of Muenster, Muenster, Germany
Yasodha Natkunam - Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
Alberto Orfao - Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
Verónica Domínguez - Transgenesis Facility CNB-CBMSO, CSIC-UAM, Madrid, Spain
Belén Pintado - Transgenesis Facility CNB-CBMSO, CSIC-UAM, Madrid, Spain
Oscar Blanco - Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain
Diego Alonso-López - Bioinformatics Unit, Cancer Research Center (CSIC-USAL), Salamanca, Spain
Javier De Las Rivas - Bioinformatics and Functional Genomics Research Group, Cancer Research Center (CSIC-USAL), Salamanca, Spain
Alberto Martín-Lorenzo - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Rafael Jiménez - Departamento de Fisiología y Farmacología, Edificio Departamental, Universidad de Salamanca, Salamanca, Spain
Francisco Javier García Criado - Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
María Begoña García Cenador - Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain
Izidore S Lossos - Department of Molecular and Cellular Pharmacology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
Carolina Vicente-Dueñas - 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
Arndt Borkhardt - 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
Julia Hauer - 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
Isidro Sánchez-García - Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
Publication Details: The EMBO journal, Vol.37(14), p.n/a
Publisher: England
Academic Unit: Miller School of Medicine; UMMG Dept of Medicine - Hematology/Oncology
Language: English
Resource Type: Journal article
PMID: 29880602
PMCID: PMC6043907
Record Identifier: 991031576342602976