Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

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. Synopsis Genetic lineage tracing in cell type‐specific mouse models of T‐cell lymphoblastic leukemia (T‐ALL) reveals that tumor cell identity is imposed by expression of the oncogene LMO2, rather than by the target cell phenotype. Maintained conditional expression of LMO2 in the hematopoietic lineage results in aggressive T‐ALL in vivo . Restricted early LMO2 expression in hematopoietic stem/progenitor cells is sufficient to induce histological, genomic and transcriptional features of human T‐ALL. Thymus deficiency impedes secondary genomic alterations required for T‐ALL development. B‐cell‐specific LMO2 expression reprograms pro‐B cells and germinal center B cells into T‐ALL cells. Graphical Abstract The tumor cell state in mouse T‐cell leukemias is dictated by LMO2 oncogene expression independently of the target cell phenotype.