Abstract
LMO2 was first discovered through proximity to frequently occurring chromosomal translocations in T cell acute lymphoblastic leukaemia (T-ALL). Subsequent studies on its role in tumours and in normal settings have highlighted LMO2 as an archetypical chromosomal translocation oncogene, activated by association with antigen receptor gene loci and a paradigm for translocation gene activation in T-ALL. The normal function of LMO2 in haematopoietic cell fate and angiogenesis suggests it is a master gene regulator exerting a dysfunctional control on differentiation following chromosomal translocations. Its importance in T cell neoplasia has been further emphasized by the recurrent findings of interstitial deletions of chromosome 11 near LMO2 and of LMO2 as a target of retroviral insertion gene activation during gene therapy trials for X chromosome-linked severe combined immuno-deficiency syndrome, both types of event leading to similar T cell leukaemia. The discovery of LMO2 in some B cell neoplasias and in some epithelial cancers suggests a more ubiquitous function as an oncogenic protein, and that the current development of novel inhibitors will be of great value in future cancer treatment. Further, the role of LMO2 in angiogenesis and in haematopoietic stem cells (HSCs) bodes well for targeting LMO2 in angiogenic disorders and in generating autologous induced HSCs for application in various clinical indications.
Highlights
Developments in molecular biology in the 1980s led to the finding that recurrent, cancer-associated chromosomal translocations result in either perturbed oncogene control resulting from joining with antibody or T cell receptor (TCR) genes or creation of novel fusion protein with chimaeric functions
X chromosomelinked severe combined immuno-deficiency syndrome (X-SCID) is caused by a defect in the Interleukin-2 receptor gamma common chain (IL2RGC), which is necessary for high-affinity signalling of
We have shown with a mouse transgenic model that concurrent expression of LMO2 and IL2RGC in thymocytes accelerates the formation of clonal T cell neoplasias compared with those arising in transgenic aberrantly expressing only LMO2, while aberrant expression of IL2RGC alone has no discernable oncogenic effect in thymocytes
Summary
Developments in molecular biology in the 1980s led to the finding that recurrent, cancer-associated chromosomal translocations result in either perturbed oncogene control resulting from joining with antibody or T cell receptor (TCR) genes or creation of novel fusion protein with chimaeric functions (reviewed in [1,2]). Studies of TCR gene rearrangement and gene location suggested that T cell cancer-associated chromosomal translocations would have oncogene activations [3]. This proved correct, and 25 years ago LMO2 was discovered, and published the following year [4,5], as a recurrent chromosomal translocation partner of TCR loci in a subset of patients with T cell acute lymphoblastic leukaemia (T-ALL).
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