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 - Publisher Copyright:
© 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 - cancer initiation
KW - epigenetic priming
KW - mouse models
KW - oncogenes
KW - stem cells
UR - http://www.scopus.com/inward/record.url?scp=85049857846&partnerID=8YFLogxK
U2 - 10.15252/embj.201798783
DO - 10.15252/embj.201798783
M3 - Article
C2 - 29880602
AN - SCOPUS:85049857846
SN - 0261-4189
VL - 37
JO - EMBO Journal
JF - EMBO Journal
IS - 14
M1 - e98783
ER -