Alternative titles; symbols
HGNC Approved Gene Symbol: LMO2
Cytogenetic location: 11p13 Genomic coordinates (GRCh38) : 11:33,858,576-33,892,076 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p13 | Leukemia, acute T-cell | 180385 | 2 |
A chromosomal translocation in a T-cell leukemia involving chromosome 11p15 disrupts the rhombotin gene (LMO1; 186921), which encodes a protein with duplicated cysteine-rich regions called LIM domains. Boehm et al. (1991) isolated a homolog of rhombotin, LMO2, which they called RHOM2. Human and mouse RHOM2 are highly conserved and, like rhombotin, encode 2 tandem cysteine-rich LIM domains. Northern blot analysis showed that Rhom2 mRNA was expressed in early mouse development and in adult central nervous system, lung, kidney, liver, and spleen, but only at low levels in thymus.
By searching for expressed sequences surrounding a T-cell acute lymphoblastic leukemia (T-ALL)-specific translocation breakpoint cluster region (see CYTOGENETICS), Royer-Pokora et al. (1991) identified LMO2, which they called TTG2. TTG2 encodes a small cysteine-rich protein that shares 48% amino acid identity with rhombotin.
By screening a fetal liver cDNA library with a TTG2 probe, Royer-Pokora et al. (1995) identified a splice variant of TTG2 with a 5-prime extension compared with the previously identified transcript. The long and short TTG2 transcripts encode identical 158-amino acid proteins with tandem LIM domains. RT-PCR suggested that expression of the long transcript was erythroid specific, whereas expression of the short transcript was ubiquitous.
By searching for genes in a region of chromosome 11 associated with WAGR syndrome (194072), Gawin et al. (1999) identified and cloned LMO2, which they designated clone 240495. Northern blot analysis of several human tissues detected a 1.9-kb LMO2 transcript predominantly expressed in placenta.
Using real-time PCR, Landry et al. (2005) found that LMO2 transcripts originating from the proximal promoter near exon 3 (i.e., short transcripts) dominated in human bone marrow, peripheral blood, and K563 cells and in mouse tissues and cells. Much weaker expression from the distal promoter upstream of exon 1 (i.e., long transcripts) was detected in hematopoietic tissues.
Using immunohistochemical analysis, Natkunam et al. (2007) showed that LMO2 was expressed in the nucleus of normal germinal-center (GC) B cells, in GC-derived B-cell lines, and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors, in megakaryocytes, and in lymphoblastic and acute myeloid leukemias. LMO2 was not expressed in any nonhematolymphoid tissues, except for endothelial cells.
Oram et al. (2010) found variable and tissue-specific expression of LMO3 from 3 promoters in normal human endothelial and blood cells, fetal kidney, liver, and thymus, and in T-ALL cell lines. Expression from the intermediate promoter between the distal and proximal promoters was not detected in normal mature T cells, but it was detected in T-ALL samples, with highest expression in cells showing the most primitive phenotype.
Mao et al. (1997) found that RBTN2 had transactivation activity against a reporter gene in yeast and in transfected COS cells when it was fused to the DNA-binding domain of GAL4. Both the N- and C-terminal regions of RBTN2 contained transactivation domains, and the 2 LIM domains functioned as transcription repressors. In context of full-length RBTN2, the LIM domains selectively repressed the N-terminal activation domain, but they had no effect on the C-terminal activation domain.
RBTN2 has distinct functions in erythropoiesis and in T-cell leukemogenesis. Additional functions for RBTN2 are indicated by its expression in nonhematopoietic tissues. These diverse functions of RBTN2 are presumed to be accomplished through physical interaction with different protein partners that bind the LIM domains of RBTN2. To identify these proteins which may modulate the activity of RBTN2, Mao et al. (1997) employed the yeast 2-hybrid assay to screen a human lymphocyte cDNA library using the RBTN2 LIM domain region as bait. They isolated a cDNA encoding the C-terminal region of the retinoblastoma-binding protein-2 (RBBP2; 180202). The authors confirmed the interaction between RBTN2 and RBBP2 using in vitro binding assays and by coimmunoprecipitation of the 2 proteins. Deletion analysis showed that the second LIM domain of RBTN2 was necessary and sufficient for binding to the last 69 amino acids of RBBP2. The interaction between RBTN2 and RBBP2 had a functional consequence: the combination of RBBP2 and RBTN2 resulted in a higher level of transcription than RBTN2 alone in an in vitro assay. Mao et al. (1997) stated that the interaction of RBTN2 with RBBP2 suggests that RBTN2 may directly affect the activity of RBBP2 and/or RBTN2 may indirectly modulate the functions of RB1 (614041) by binding to RBBP2.
By yeast 2-hybrid screening, Wilkinson et al. (1997) showed that mouse Elf2 (619798) bound to Rbtn2. Both LIM domains of Rbtn2 were necessary and sufficient for binding Elf2.
Using microarray analysis of gene expression signatures, Lossos et al. (2004) studied prediction of prognosis in diffuse large B-cell lymphoma. In a univariate analysis, genes were ranked on the basis of their ability to predict survival; the strongest predictors of longer overall survival were LMO2, BCL6 (109565), and FN1 (135600), and the strongest predictors of shorter overall survival were CCND2 (123833), SCYA3 (182283), and BCL2 (151430). Lossos et al. (2004) developed a multivariate model that was based on the expression of these 6 genes, and validated the model in 2 independent microarray data sets. The model was independent of the International Prognostic Index and added to its predictive power.
Using a yeast 2-hybrid system with a human fetal brain cDNA library, Han et al. (2005) found that LMO2 interacted with human BEX2 (300691), but not with mouse Bex1 (300690) or Bex2. Protein pull-down and coimmunoprecipitation assays confirmed the interaction between LMO2 and BEX2. Electrophoretic mobility shift assays showed that BEX2 and LMO2 were part of a DNA-binding complex that recognized the E-box element. Other components of this complex included NSCL2 (NHLH2; 162361) and LDB1 (603451). LMO2 directly bound NSCL2 and upregulated NSCL2-dependent transcriptional activity, and BEX2 augmented this effect.
Landry et al. (2005) stated that LMO2 interacts with transcription factors in multiprotein complexes in a cell- and tissue-specific manner. Using chromatin immunoprecipitation analysis, they found that the ETS transcription factors Elf1 (189973), Fli1 (193067), Ets1 (164720), and Ets2 (164740) bound to the mouse Lmo2 proximal promoter in hematopoietic progenitors. Elf1, Fli1, and Ets1, but not Ets2, bound the Lmo2 proximal promoter in endothelial cells. The Lmo2 proximal promoter drove endothelial expression of a marker gene in transgenic mice.
Using transgenic mice, Oram et al. (2010) found that expression of human LMO2 from the intermediate promoter, like that from the distal and proximal promoters, required downstream enhancer elements. Binding studies and reporter gene assays revealed that ERG (165080) and FLI1 (193067) bound and activated the LMO2 intermediate promoter in T-ALL samples. LMO2 also bound enhancers in the FLI1 and ERG loci, and all 3 proteins bound an enhancer element in the first intron of the hematopoietically expressed HHEX gene (604420) and upregulated expression of an HHEX reporter gene. Oram et al. (2010) proposed that a self-sustaining triad of LMO2, ERG, and FLI1 are involved in T-ALL by stabilizing HHEX expression.
Role of LMO2 in Gene Therapy of SCIDX1
Hacein-Bey-Abina et al. (2003) reported a patient with X-linked severe combined immunodeficiency disease (SCIDX1; 300400) treated by ex vivo, retrovirally mediated transfer of the gene defective in this disorder, gamma-c (IL2RG; 308380). Apparent insertional mutagenesis occurred due to proviral integration on 11p within the LMO2 locus, and the patient developed acute lymphoblastic leukemia.
Hacein-Bey-Abina et al. (2003) demonstrated that in the 2 patients who developed T-cell leukemia after retrovirus-mediated gene transfer into autologous CD34 cells, the retrovirus vector integration was in proximity to the LMO2 protooncogene promoter, leading to aberrant transcription and expression of LMO2. Hacein-Bey-Abina et al. (2003) speculated that SCIDX1-related features may have contributed to the unexpectedly high rate of leukemia-like syndrome in their gene therapy-treated patients. They speculated that, because of the differentiation block, there are more T-lymphocyte precursors among CD34 cells in SCIDX1 marrow than in marrow of normal controls, thus augmenting the number of cells at risk for vector integration and further proliferation once the gamma-c transgene is expressed.
By searching a database containing the sequences of more than 3,000 retroviral integration sites cloned from mouse retrovirally induced hematopoietic tumors, Dave et al. (2004) identified 2 leukemias with integrations at Lmo2 and 2 leukemias with integrations at Il2rg. One of these leukemias contained integrations at both sites. These integrations were clonal, suggesting that they were acquired early during the establishment of the leukemia. The probability of finding a leukemia with clonal integrations at Lmo2 and Il2rg by random chance is exceedingly small, providing genetic evidence for cooperativity between LMO2 and IL2RG. Leukemia 98-031 had a T cell phenotype and upregulated Lmo2 expression, a finding consistent with that seen in SCIDX1 patient leukemias. Dave et al. (2004) suggested that the results provide a genetic explanation for the high frequency of leukemia in these gene therapy trials. In transplant patients, IL2RG is expressed from the ubiquitous Moloney viral long terminal repeat. Although this was expected to be safe, Dave et al. (2004) concluded that retrovirally expressed IL2RG might be oncogenic due to some subtle effect on growth or differentiation of infected cells. Dave et al. (2004) further concluded that their results boded well for future gene therapy trials, because in most trials the transplanted gene is unlikely to be oncogenic and occurrences of insertional mutagenesis will be low. Berns (2004) likewise took the view that the findings of Dave et al. (2004) represented 'good news for gene therapy.'
McCormack and Rabbitts (2004) reviewed the mechanism of LMO2 leukemogenesis and involvement of LMO2 in gene therapy of SCIDX1.
Royer-Pokora et al. (1995) determined that the LMO2 gene contains 6 exons and spans about 35 kb. LMO2 has a distal promoter upstream of exon 1 and proximal promoter upstream of exon 3, with a translational start site in exon 4. The distal promoter lacks TATA and CCAAT elements, but it has a consensus initiator element, a GC box, an Sp1 (189906)-binding site, and 2 GATA (see 305371)-binding sites. Of 1 these elements, a GATA box, is conserved in rodents.
Oram et al. (2010) identified a functional intermediate promoter and enhancer element between the distal and proximal promoters in the LMO2 gene. This intermediate promoter is conserved in mammals.
By somatic cell hybrid analysis, Boehm et al. (1991) mapped the LMO2 gene to chromosome 11p13.
Boehm et al. (1991) found that the RHOM2 gene maps to chromosome 11p13, where a cluster of T-ALL-specific translocations occur. They determined that the translocation breakpoints in the T-ALL cluster occurred at the 5-prime end of the RHOM2 gene, within 25 kb of the presumed transcriptional start site.
Royer-Pokora et al. (1991) cloned 70 kb of DNA from chromosome 11p13 at the site of a recurrent t(11;14)(p13;q11) translocation in T-ALL involving the TCR-delta locus (see 186810) on chromosome 14q11. They identified 2 new and 10 previously identified translocations mapping within 25 kb of each other on 11p13 and constituting the so-called 11p13 T-cell translocation cluster (11p13 ttc). Royer-Pokora et al. (1991) found that the TTG2 gene was telomeric of all breakpoints and was overexpressed in 3 T-ALL samples with a t(11;14).
The LIM-finger protein Lmo2, which is activated in T-cell leukemias by chromosomal translocations, is required for yolk sac erythropoiesis. Because Lmo2-null mice died at embryonic day 9 to 10, assessment of a role in other stages of hematopoiesis was impossible. Yamada et al. (1998) studied the hematopoietic contribution of homozygous mutant Lmo2 -/- mouse embryonic stem cells and found that these cells did not contribute to any hematopoietic lineage in adult chimeric mice, but reintroduction of an Lmo2-expression vector rescued the ability of Lmo2-null embryonic stem cells to contribute to all lineages tested. Yamada et al. (1998) stated that this disruption of hematopoiesis probably occurs because interaction of the Lmo2 protein with factors such as Tal1/Scl (187040) is precluded. Thus, Lmo2 is necessary for early stages of hematopoiesis, and the Lmo2 master gene encodes a protein that has a central and crucial role in hematopoietic development.
To assess a possible function of Lmo2 in transcriptional regulation of vascular development and consequent blood cell specification, Yamada et al. (2000) studied formation of the vascular system in mouse chimeras generated with Lmo2-null embryonic stem (ES) cells. The fate of ES-derived cells after injection into blastocysts was followed in embryonic vasculogenesis and angiogenesis by means of beta-galactosidase expressed from the Lmo2 promoter. Comparing heterozygous- and homozygous-null Lmo2 ES cell fate, they observed that Lmo2 was expressed in endothelial cells during mouse embryogenesis and that vasculogenesis proceeded normally in the absence of Lmo2. However, the Lmo2 gene plays a critical role in the construction of the mature vascular network (angiogenesis), because this process did not occur in chimeras with a high contribution from Lmo2-null ES cells.
To investigate the cellular origin of LMO2-induced leukemia, McCormack et al. (2010) used cell fate mapping to study mice in which the Lmo2 gene was constitutively expressed in the thymus. Lmo2 induced self-renewal of committed T cells in the mice more than 8 months before the development of overt T-ALL. These self-renewing cells retained the capacity for T cell differentiation but expressed several genes typical of hematopoietic stem cells, suggesting that Lmo2 might reactivate a hematopoietic stem cell-specific transcriptional program. Forced expression of one such gene, Hhex (604420), was sufficient to initiate self-renewal of thymocytes in vivo. McCormack et al. (2010) concluded that Lmo2 promotes the self-renewal of preleukemic thymocytes, providing a mechanism by which committed T cells can then accumulate additional genetic mutations required for leukemic transformation.
TCL2 was the prior designation for the LMO2 gene, which can be activated by translocation of part of the TCRA gene (see 186880) to its vicinity in cases of acute T-cell leukemia (Showe and Croce, 1986; Erikson et al., 1985; and Lewis et al., 1985).
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