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

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.

SUBMITTER: Garcia-Ramirez I

PROVIDER: S-EPMC6043907 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

García-Ramírez Idoia I Bhatia Sanil S Rodríguez-Hernández Guillermo G González-Herrero Inés I Walter Carolin C González de Tena-Dávila Sara S Parvin Salma S Haas Oskar O Woessmann Wilhelm W Stanulla Martin M Schrappe Martin M Dugas Martin M Natkunam Yasodha Y Orfao Alberto A Domínguez Verónica V Pintado Belén B Blanco Oscar O Alonso-López Diego D De Las Rivas Javier J Martín-Lorenzo Alberto A Jiménez Rafael R García Criado Francisco Javier FJ García Cenador María Begoña MB Lossos Izidore S IS Vicente-Dueñas Carolina C Borkhardt Arndt A Hauer Julia J Sánchez-García Isidro I

The EMBO journal 20180607 14

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 hemat ...[more]

PMID: 29880602

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

Publications

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

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