Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

Abstract

[EN]The impact of LMO2expression on cell lineage decisions duringT-cell leukemogenesis remains largely elusive. Using geneticlineage tracing, we have explored the potential of LMO2in dictat-ing a T-cell malignant phenotype. We first initiated LMO2expres-sion in hematopoietic stem/progenitor cells and maintained itsexpression in all hematopoietic cells. These mice develop exclu-sively aggressive human-like T-ALL. In order to uncover a potentialexclusive reprogramming effect of LMO2in murine hematopoieticstem/progenitor cells, we next showed that transient LMO2expression is sufficient for oncogenic function and induction ofT-ALL. The resulting T-ALLs lacked LMO2and its target-geneexpression, and histologically, transcriptionally, and geneticallysimilar to human LMO2-driven T-ALL. We next found that during T-ALL development, secondary genomic alterations take place withinthe thymus. However, the permissiveness for development of T-ALLseems to be associated with wider windows of differentiation thanpreviously appreciated. Restricted Cre-mediated activation ofLmo2at different stages of B-cell development induces systemati-cally and unexpectedly T-ALL that closely resembled those of theirnatural counterparts. Together, these results provide a novel para-digm for the generation of tumor T cells through reprogrammingin vivoand could be relevant to improve the response of T-ALL tocurrent therapies.