Murine Leukemias with Retroviral Insertions at Lmo2 Are Predictive of the Leukemias Induced in SCID-X1 Patients Following Retroviral Gene Therapy

Abstract

Five X-linked severe combined immunodeficiency patients (SCID-X1) successfully treated with autologous bone marrow stem cells infected ex vivo with an IL2RG-containing retrovirus subsequently developed T-cell leukemia and four contained insertional mutations at LMO2. Genetic evidence also suggests a role for IL2RG in tumor formation, although this remains controversial. Here, we show that the genes and signaling pathways deregulated in murine leukemias with retroviral insertions at Lmo2 are similar to those deregulated in human leukemias with high LMO2 expression and are highly predictive of the leukemias induced in SCID-X1 patients. We also provide additional evidence supporting the notion that IL2RG and LMO2 cooperate in leukemia induction but are not sufficient and require additional cooperating mutations. The highly concordant nature of the genetic events giving rise to mouse and human leukemias with mutations at Lmo2 are an encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for retroviral gene therapy.

A previously unrecognized promoter of LMO2 forms part of a transcriptional regulatory circuit mediating LMO2 expression in a subset of T-acute lymphoblastic leukaemia patients

“…Expression profiling of pre-leukaemic and wildtype thymocytes, and human T-ALL samples identified a gene-expression signature containing candidates with known roles in haematopoietic stem cell function, and a bone marrow reconstitution model showed that HHEX/ PRH overexpression recapitulated the oncogenic potential of lmo2. Dave et al (2009) andMcCormack et al (2010) both suggest a possible role of the LMO2-ETS factor interaction and identify HHEX/PRH as a potential downstream collaborator in mice. However, although these studies have identified lmo2, the ETS factors and HHEX/PRH as collaborating oncogenes, they do not distinguish whether they function in a parallel, overlapping or hierarchical manner.…”

“…Recent work from insertional mutagenesis models in mice (Dave et al, 2009) has shown that the genes and signalling pathways deregulated in murine leukaemias with retroviral insertions at LMO2 are analogous to both those dysregulated in highly LMO2-expressing human leukaemias (Ferrando et al, 2002;Yeoh et al, 2002;Chiaretti et al, 2004) and to the LMO2 retroviral insertion-mediated leukaemias induced in severe combined immunodeficiency-X1 patients (Hacein-BeyAbina et al, 2003a, b, 2008. Moreover, many of these genes are components of haematopoietic stem cell transcriptional regulatory networks.…”

“…LMO2 overexpression is seen most consistently in the more immature T-ALL phenotypes (van Grotel et al, 2008), which have previously been associated with poor treatment outcome (Crist and Pui, 1993;Garand and Bene, 1993). Importantly, ectopic LMO2 expression due to transcriptional activation following retroviral vector integration into the LMO2 locus has also been implicated in the development of clonal T-cell proliferation and subsequent T-ALL in patients undergoing gene therapy for X-linked severe combined immunodeficiency (Hacein-Bey-Abina et al, 2003bHowe et al, 2008), and this has recently been recapitulated using murine retroviral mutagenesis models (Dave et al, 2009). Taken together, the evidence from T-ALL patients, the transgenic mouse models and the insertional mutagenesis observations suggest that aberrant LMO2 expression in an immature haematopoietic cell represents a 'first-hit' to cause an accumulation of early lymphoid precursors with subsequent progression to T-ALL.…”

“…The ETS transcription factors ERG and FLI1 bind to the LMO2 intermediate promoter and LMO2, ERG and FLI1 can form protein-protein complexes The ETS family transcription factor FLI1 was recently identified as a candidate collaborating oncogene of LMO2 in retroviral mutagenesis models of T-ALL (Dave et al, 2009). We therefore investigated potential interactions between LMO2 and FLI1 in human T-ALL.…”

The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells

“…19,20 In support of this hypothesis, several reports have shown a striking correlation between LMO2, TAL1, and Olig2 based on gene expression analysis in human and murine T-cell leukemia. [21][22][23] In future studies, it will be interesting to explore whether LMO2 interacts with Olig2 to regulate GSCs and brain tumorigenesis. Presence of tumor-derived vascular components sheds light on the plasticity of cancer cells and the potential involvement of cancer stem cells in cancer-associated angiogenesis.…”