Lmo2 expression defines tumor cell identity during T-cell leukemogenesis

TY - JOUR

T1 - Lmo2 expression defines tumor cell identity during T-cell leukemogenesis

AU - García-Ramírez, Idoia

AU - Bhatia, Sanil

AU - Rodríguez-Hernández, Guillermo

AU - González-Herrero, Inés

AU - Walter, Carolin

AU - González de Tena-Dávila, Sara

AU - Parvin, Salma

AU - Haas, Oskar

AU - Woessmann, Wilhelm

AU - Stanulla, Martin

AU - Schrappe, Martin

AU - Dugas, Martin

AU - Natkunam, Yasodha

AU - Orfao, Alberto

AU - Domínguez, Verónica

AU - Pintado, Belén

AU - Blanco, Oscar

AU - Alonso-López, Diego

AU - De Las Rivas, Javier

AU - Martín-Lorenzo, Alberto

AU - Jiménez, Rafael

AU - García Criado, Francisco Javier

AU - García Cenador, María Begoña

AU - Lossos, Izidore S

AU - Vicente-Dueñas, Carolina

AU - Borkhardt, Arndt

AU - Hauer, Julia

AU - Sánchez-García, Isidro

N1 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

PY - 2018/7/13

Y1 - 2018/7/13

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.15252/embj.201798783

DO - 10.15252/embj.201798783

M3 - SCORING: Journal article

C2 - 29880602

VL - 37

JO - EMBO J

JF - EMBO J

SN - 0261-4189

IS - 14

ER -