Disease relevance of LMO2

• Some T cell leukaemia patients have chromosomal abnormalities involving both genes, implying that LMO2 and TAL1 act synergistically to promote tumorigenesis after their inappropriate co-expression [1].
• The overexpression of LIM-only protein 2 (LMO2) in T-cells, as a result of chromosomal translocations, retroviral insertion during gene therapy, or in transgenic mice models, leads to the onset of T-cell leukemias [2].
• We used mutagenesis in combination with yeast two-hybrid analysis, and phage display selection to identify LMO2-binding "hot spots" within Ldb1 that locate to the LIM1-binding region [2].
• Our data help explain why LMO2 was preferentially targeted over many of the other known T-ALL oncogenes [3].
• Although retroviral integration near the T-cell acute lymphoblastic leukemia (T-ALL) oncogene LIM-only protein 2 (LMO2) appears to be a common event, it is unclear why LMO2 was preferentially targeted [3].
• The position of the LMO2 breakpoints in T-ALL in the light of the occurrence of TCRD-LMO2 translocations in normal thymocytes points to a critical role for the exact breakpoint location in determining LMO2 activation levels and the consequent pressure for T-ALL development [4].

High impact information on LMO2

• The LIM domain protein rbtn2 is associated with T cell acute leukemias [5].
• The homozygous rbtn2 null mutation leads to failure of yolk sac erythropoiesis and embryonic lethality around E10 [5].
• Cooperation between the stem cell leukemia (SCL) transcription factor and its nuclear partners LMO1 or LMO2 induces aggressive T cell acute lymphoblastic leukemia when inappropriately expressed in T cells [6].
• Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus [7].
• LMO2 and LMO4 are members of a small family of nuclear transcriptional regulators that are important for both normal development and disease processes [8].

Chemical compound and disease context of LMO2

• Combination of all-trans retinoic acid and lithium chloride surmounts a retinoid differentiation block induced by expression of Scl and Rbtn2 transcription factors in myeloid leukemia cells [9].

Biological context of LMO2

• The LMO2 and TAL1 genes were first identified via chromosomal translocations and later found to encode proteins that interact during normal erythroid development [1].
• 3. This chromosome location is of interest as it occurs in a region that is deleted in a number of human cancers, indicating a possible role of LMO4 in tumorigenesis, like its relatives LMO1 and LMO2 [10].
• To identify these proteins which may modulate the activity of RBTN2, a human cDNA library was screened using the yeast two-hybrid assay [11].
• The nuclear LIM domain protein LMO2, a T cell oncoprotein, is essential for embryonic erythropoiesis [12].
• Recent reports linking insertional activation of LMO2 following gene therapy for X-linked severe combined immunodeficiency (X-SCID) have led to a re-evaluation of risks following gene therapy with retroviral vectors [13].

Anatomical context of LMO2

• We show that of classical T-ALL oncogenes, LMO2 is most highly transcribed in CD34+ progenitor cells [3].
• In contrast, retroviral overexpression of LMO2 in CD34+ cells caused severe abnormalities in T-cell development, but B-cell and myeloid development remained unaffected [3].
• The LIM domain-only genes LMO1 and LMO2 are translocated in acute T cell leukemia (T-ALL) and have been shown to be oncogenes in T lymphoid cells [14].
• During jaw and limb outgrowth, LMO4 and LMO2 expression define mesenchyme that is uncommitted to regional fates [15].
• LMO2 is necessary for development of the entire hematopoietic system and overexpression of LMO1 or LMO2 results in human acute T cell leukemia [16].

Associations of LMO2 with chemical compounds

• The use of yeast assays with RBTN2 shows that RBTN2 forms homodimers and that the NH2-terminal 27 amino acids are sufficient to facilitate transcriptional transactivation [17].
• Addition of LiCl to ATRA treatment restored the capacity of both Scl- and Rbtn2-expressing cells to respond to the retinoid in a synergistic manner [9].

Physical interactions of LMO2

• T-cell oncogene rhombotin-2 interacts with retinoblastoma-binding protein 2 [11].
• By mammalian two-hybrid analysis, we show that HEN1 interacts with both LMO2 and LMO4 [18].
• By using mammalian two-hybrid analysis, E47/Tall/Lmo2/GATA-1 protein complex could be demonstrated [19].
• We used the yeast two-hybrid system to identify novel Lmo2 interacting proteins and found that the AF6 protein binds to Lmo2 [20].

Regulatory relationships of LMO2

• We have also shown that hBex2 can enhance the transcriptional activity of LMO2 in vivo [21].
• LMO2 has been shown to cause tumours when aberrantly expressed and to be able to heterodimerise with TAL1 to facilitate tumour development [22].

Other interactions of LMO2

• RBTN1 and RBTN2 encode highly related proteins that possess cysteine-rich LIM motifs [23].
• The oncogenic functions of LMO1 and LMO2 are thought to be mediated by interaction with LDB1 since they form a multimeric protein complex(es) [10].
• The interleukin-2 receptor gamma chain (IL2Rgamma), which is mutated in SCID-X1, has been proposed as a cooperating oncogene to LMO2 [3].
• Instead, restoration of normal IL7-receptor signaling may allow progression of T-cell development to stages where ectopic LMO2 expression causes aberrant thymocyte growth.Leukemia (2007) 21, 754-763. doi:10.1038/sj.leu.2404563; published online 1 February 2007 [3].
• Using electrophoretic mobility shift assay, we have demonstrated the physical interaction of hBex2 and LMO2 as part of a DNA-binding protein complex [21].

Analytical, diagnostic and therapeutic context of LMO2

• Here, we show using protein engineering and enzyme-linked immunosorbent assay (ELISA) methodologies that LMO2 binds Ldb1 with a twofold lower affinity than does LMO4 [2].
• The interaction between RBTN2 and RBP2 was confirmed using in vitro binding assays, and by co-immunoprecipitation of the two proteins [11].
• These data were supported by quantitative real-time PCR experiments, where LMO2 mRNA levels were found to be significantly higher in prostate tumour specimen than in normal epithelium (p = 0.037) [24].
• The expression of LMO2 in cell lines and xenografts representing androgen-dependent (AD) and androgen-independent (AI) prostate cancer stages was further studied [24].
• Interestingly we observed that the Dlmo protein is immunologically related to LMO-2 and can be detected by immunohistochemistry in early cellular blastoderm embryos [25].

References