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 - Funding Information:
We are indebted to all members of our groups for useful discussions and for their critical reading of the manuscript. J.H. has been supported by the German Cancer Aid (Project 110997 and Translational Oncology Program 70112951), the German Jose Carreras Leukemia Foundation (DJCLS 02R/ 2016), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Joint funding (Targeting MYC L*10), the Kinderkrebsstiftung (2016/17), and the “Elterninitiative Kinderkrebsklinik e.V. Düsseldorf”. SG has been supported by a scholarship of the Hochschule Bonn-Rhein-Sieg. AB has been supported by the German Children’s Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in ISG group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R, and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII-Plan de Ayudas IBSAL 2015 Proyec-tos Integrados (IBY15/00003), by Junta de Castilla y León (BIO/SA51/15, CSI001U14, UIC-017, and CSI001U16), Fundacion Inocente Inocente, and by the ARIMMORA project (European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282891). ISG Lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. AB and ISG have been supported by the German Carreras Foundation (DJCLS R13/26). IGR was supported by BES-Ministerio de Economía y Competitividad (BES-2013-063789). AML and GRH were supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13, CSI001-15). Research in CVD group is partially supported by FEDER, “Miguel Servet” Grant (CP14/00082—AES 2013-2016) from the Insti-tuto de Salud Carlos III (Ministerio de Economía y Competitividad), “Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III” (PI17/00167), and by the Lady Tata International Award for Research in Leukaemia 2016– 2017.
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
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U2 - 10.15252/embj.201798783
DO - 10.15252/embj.201798783
M3 - Article
C2 - 29880602
AN - SCOPUS:85049857846
VL - 37
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 14
M1 - e98783
ER -