Lmo2 expression defines tumor cell identity during T-cell leukemogenesis
Summary
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. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.
| Authors | 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, Martín-Lorenzo A, Jiménez R, García Criado FJ, García Cenador MB, Lossos IS, Vicente-Dueñas C, Borkhardt A, Hauer J, Sánchez-García I |
|---|---|
| Journal | The EMBO journal |
| Publication Date | 2018 Jul 13;37(14) |
| PubMed | 29880602 |
| PubMed Central | PMC6043907 |
| DOI | 10.15252/embj.201798783 |