LMO2 at 25 years: a paradigm of chromosomal translocation proteins

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.

Superenhancer reprogramming drives a B-cell–epithelial transition and high-risk leukemia

“…Extralineage transcription factors directly repressed by IKAROS and occupying the de novo enhancer network included LMO2, a pioneer factor in iHSC that is associated with hematopoietic stem cell self-renewal, early lineage decisions, and B-cell precursor leukemias (Riddell et al 2014;Chambers and Rabbitts 2015); YAP1 and TEAD (1/2), the nuclear effectors of the Hippo pathway implicated in growth and self-renewal in a variety of nonlymphoid cell types; and LHX2, a pioneer factor in neuronal and skin epithelial stem cells (Rhee et al 2006;Salvatierra et al 2014;Adam et al 2015;Yu et al 2015). Notably, with the exception of LMO2, these extralineage transcription factors are direct targets of EBF1 in IKDN pre-B cells.…”

Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia

“…1 In mice, Lmo2 is progressively silenced after the early T-cell progenitor (ETP) stage of thymic development and leads to T-cell acute lymphoblastic leukemia (T-ALL) when overexpressed in transgenic models. [2][3][4] In human thymi, LMO2 is similarly downregulated after commitment to the T-cell lineage as indicated by DNA microarray analyses.…”

Transcriptional circuits in B cell transformation

“…Super-enhancers are defined as clusters of binding sites for master transcription regulators, are highly enriched for active histone modifications and the Mediator complex, and are responsible for expression of genes that specify a new cell identity [25–27]. Among the group of extra-lineage transcription factors were; LMO2, associated with hematopoietic stem cell self-renewal, early hematopoietic lineage decisions as well as T and B cell precursor leukemias [28,29]; YAP1 and TEAD (1/2), the nuclear effectors of the Hippo pathway implicated in growth and self-renewal in non-lymphoid cell types and responsible for super-enhancer activation through recruitment of the Mediator and the CDK9 elongation complex [30,31]; and LHX2 a pioneer factor in neuronal and skin epithelial stem cells [32–34]. Notably, B cell master regulators (e.g.…”