Lmo2 expression defines tumor cell identity during T‐cell leukemogenesis

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.

T-cell leukemogenesis is an inappropriate lineage decision-making process: implications for precision oncology

“…The resulting T-ALL lacked Lmo2 and its targeted-gene expression, and were histologically, transcriptionally and genetically similar to human LMO2 driven T-ALL in which LMO2 alterations are frequently observed. 5 These results therefore confirm that activity of the Lmo2 oncogene restricted to HS/PCs can induce malignancies in mice that are of a T-cell stage of differentiation. However, the permissiveness for development of T-ALL seems to be associated with wider windows of differentiation than previously appreciated.…”

“…8,9 Similarly, a significant proportion of T-ALL in all our murine models carried p53 loss-of-function mutations facilitating pathological reprogramming to a malignant T-cell phenotype. 5 In conclusion, we have provided the first evidence of a 'hit-and-run' role for Lmo2 in the oncogenesis of T-ALL. The implication of these findings led us to propose that T-ALL is the result of an inappropriate lineagedecision making process occurring via a reprogramming-like mechanism.…”

“…To test this hypothesis, we generated genetic lineage tracing strains of mice with restricted expression of this oncogene within HS/ PCs. 5 Despite lack of Lmo2 protein expression within T-cells, these mice develop aggressive and clonal T-ALL. The resulting T-ALL lacked Lmo2 and its targeted-gene expression, and were histologically, transcriptionally and genetically similar to human LMO2 driven T-ALL in which LMO2 alterations are frequently observed.…”

“…Restricted Cremediated activation of Lmo2 at different stages of B-cell development induced systematically and unexpectedly T-ALL that closely resembled those of their natural counterparts. 5 Biological barriers exist to prevent cells from changing their identity in this manner in order to avoid the risk of malignant transformation. 1,6,7 In B-cell malignancies has been shown that loss of p53 is a frequent occurrence and facilitates the pathological reprogramming to a malignant B-cell phenotype.…”

“…Thus we next trace where and when these second hits appeared and found that the secondary mutations, like Notch1 mutations, appeared late and only took place within the thymus during T-ALL development. 5 This may provide an explanation for the failure of some modern targeted therapies to clear tumor stem cells, despite being effective agents against evolved tumor cells. For instance, NOTCH1 has emerged as a potentially important therapeutic target in recent years given its frequent involvement in T-ALL and the fact that specific NOTCH1 inhibitors can kill T-ALL cells in vitro and in vivo.…”