Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

• Idoia García‐Ramírez ^[1] ; Sanil Bhatia ^[7] ; Guillermo Rodríguez‐Hernández ^[1] ; Inés González‐Herrero ^[1] ; Carolin Walter ^[2] ; Sara González de Tena‐Dávila ^[1] ; Salma Parvin ^[3] ; Oskar Haas ^[8] ; Wilhelm Woessmann ^[9] ; Martin Stanulla ^[4] ; Martin Schrappe ^[10] ; Martin Dugas ^[2] ; Yasodha Natkunam ^[5] ; Alberto Orfao ^[1] ; Verónica Domínguez ^[11] ; Belén Pintado ^[11] ; Diego Alonso‐López ^[12] ; Óscar Blanco Múnez ^[1] ; Javier De Las Rivas ^[1] ; María Begoña García Cenador ^[1] ; Alberto Martín‐Lorenzo ^[1] ; Rafael Jiménez Fernández ^[1] ; Francisco Javier García Criado ^[1] ; Izidore S Lossos ^[3] ; Carolina Vicente‐Dueñas ^[6] ; Arndt Borkhardt ^[7] ; Julia Hauer ^[7] ; Isidro Sánchez‐García ^[1]
  1. [1] Instituto de Investigación Biomédica de Salamanca

     Instituto de Investigación Biomédica de Salamanca

     Salamanca, España

     
  2. [2] University Hospital Muenster

     University Hospital Muenster

     Kreisfreie Stadt Münster, Alemania

     
  3. [3] University of Miami

     University of Miami

     Estados Unidos

     
  4. [4] Hannover Medical School

     Hannover Medical School

     Region Hannover, Alemania

     
  5. [5] Stanford University

     Stanford University

     Estados Unidos

     
  6. [6] Instituto de Investigaciones Biomédicas de Barcelona

     Instituto de Investigaciones Biomédicas de Barcelona

     Barcelona, España

     
  7. [7] 3 Department of Pediatric Oncology, Hematology and Clinical Immunology Medical Faculty Heinrich‐Heine University Dusseldorf Dusseldorf Germany
  8. [8] 7 Children's Cancer Research Institute St Anna Children's Hospital Vienna Austria
  9. [9] 8 Department of Pediatric Hematology and Oncology Justus‐Liebig‐University Giessen Giessen Germany
  10. [10] 10 Department of Pediatrics Christian‐Albrechts‐University of Kiel and University Medical Center Schleswig‐Holstein Kiel Germany
  11. [11] 13 Transgenesis Facility CNB‐CBMSO CSIC‐UAM Madrid Spain
  12. [12] 15 Bioinformatics Unit Cancer Research Center (CSIC‐USAL) Salamanca Spain

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 37, Nº. 14, 2018, págs. 9-9
• Idioma: inglés
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• Resumen

  • 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.