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

Idoia García-Ramírez ,Verónica Domínguez,María Begoña García Cenador,Carolin Walter,Arndt Borkhardt,Salma Parvin,Francisco Javier García Criado,Martin Schrappe,Yasodha Natkunam,Sanil Bhatia,Julia Hauer,Wilhelm Woessmann,Martin Dugas,Javier De Las Rivas,Martin Stanulla,Rafael Jiménez,Izidore S Lossos ,Óscar Blanco ,Inés González-Herrero ,Carolina Vicente-Dueñas ,Alberto Martín-Lorenzo ,Guillermo Rodríguez-Hernández ,Alberto Órfão ,Sara González De Tena-Dávila ,Diego Alonso-López ,B Pintado ,Oskar A Haas ,Isidro Sánchez-Garcı́a

doi:10.15252/embj.201798783

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.

Highlights

The identification of the cell-of-origin from which acute lymphoblastic leukemia (ALL) initially arises is of great importance, both for our understanding of the basic biology of tumors and for the translation of this knowledge to the prevention, treatment, and precise prognosis of ALL (Visvader, 2011)
By using in vivo genetic lineage tracing, we show that Lmo2 expression in hematopoietic stem/progenitor cells (HSC/PC) as well as a precursor and mature B cells causes reprogramming and induction of T-ALL
Understanding the stepwise events taking place during tumor cell evolution is difficult, because of many genetic alterations that become clonally selected by the time of clinically manifested T-ALL (Nowell, 1976)

Summary

Introduction

The identification of the cell-of-origin from which acute lymphoblastic leukemia (ALL) initially arises is of great importance, both for our understanding of the basic biology of tumors and for the translation of this knowledge to the prevention, treatment, and precise prognosis of ALL (Visvader, 2011). Several transcriptome studies have shown that the molecular characteristics of leukemic cells do not correspond, in many cases, to what they seem to be according to their immunophenotype (Lim et al, 2009; Gilbertson, 2011) For this reason, extrapolating the identity of the cancer cell-of-origin from the ALL phenotype, without appropriate functional lineage tracing, can lead to the wrong conclusions (Molyneux et al, 2010). Thereby the differentiation state of the tumor cell-oforigin influences the frequency and latency of T-ALL These findings unveil a novel role of Lmo expression and demonstrate that Lmo promotes tumorigenesis in a manner contrasting that of other traditional oncogenes, which are persistently active in fully evolved tumor cells (Weinstein, 2002)

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Conclusion