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-LorenzoRafael Jiménez, Francisco Javier García Criado, María Begoña García Cenador, Izidore S. Lossos, Carolina Vicente-Dueñas, Arndt Borkhardt, Julia Hauer, Isidro Sánchez-García

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Article numbere98783
JournalEMBO Journal
Volume37
Issue number14
DOIs
StatePublished - Jul 13 2018

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    García-Ramírez, I., Bhatia, S., Rodríguez-Hernández, G., González-Herrero, I., Walter, C., González de Tena-Dávila, S., Parvin, S., Haas, O., Woessmann, W., Stanulla, M., Schrappe, M., Dugas, M., Natkunam, Y., Orfao, A., Domínguez, V., Pintado, B., Blanco, O., Alonso-López, D., De Las Rivas, J., ... Sánchez-García, I. (2018). Lmo2 expression defines tumor cell identity during T-cell leukemogenesis. EMBO Journal, 37(14), [e98783]. https://doi.org/10.15252/embj.201798783