LMO2 explained

LIM domain only 2 (rhombotin-like 1), also known as LMO2, RBTNL1, RBTN2, RHOM2, LIM Domain Only Protein 2, TTG2, and T-Cell Translocation Protein 2, is a protein which in humans is encoded by the LMO2 gene.^[1]

Function

LMO2 encodes a cysteine-rich, two LIM domain protein that is required for yolk sac erythropoiesis.^[2] The LMO2 protein has a central and crucial role in hematopoietic development and is highly conserved.

Clinical significance

Aberrant LMO2 expression is a significant feature of T cell acute lymphoblastic leukaemia with multiple described mechanisms of activation.^{[1] [3]} The LMO2 transcription start site is located approximately 25 kb downstream from the 11p13 T-cell translocation cluster (11p13 ttc), where a number of T-cell acute lymphoblastic leukemia-specific translocations occur. An upstream noncoding DNA element is also the site of recurrent mutations in T cell acute lymphoblastic leukaemia, leading the recruitment of the transcription factor MYB and significant H3K27ac enrichment and thus the formation of an aberrant enhancer which up-regulates the expression of LMO2 ^[4] Furthermore, recurrent and somatically acquired mutations of LMO2 intron 1 lead to its over-expression in both adult and paediatric T cell acute lymphoblastic leukaemia.^[5] These mutations introduce new transcription factor binding sites for MYB, ETS1 and RUNX1 allowing for the formation of an aberrant promoter which drives LMO2 expression.

Interactions

LMO2 has been shown to interact with:

• GATA1,^[6]
• GATA2,^[6]
• JARID1A,^[7]
• MLLT4,^[8] and
• TAL1^{[6] [9] [10] [11]}

Further reading

• Royer-Pokora B, Loos U, Ludwig WD . TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11) . Oncogene . 6 . 10 . 1887–1893 . October 1991 . 1923511 .
• Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH . The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13 . Proceedings of the National Academy of Sciences of the United States of America . 88 . 10 . 4367–4371 . May 1991 . 2034676 . 51660 . 10.1073/pnas.88.10.4367 . free . 1991PNAS...88.4367B .
• Boehm T, Spillantini MG, Sofroniew MV, Surani MA, Rabbitts TH . Developmentally regulated and tissue specific expression of mRNAs encoding the two alternative forms of the LIM domain oncogene rhombotin: evidence for thymus expression . Oncogene . 6 . 5 . 695–703 . May 1991 . 2052354 .
• Dong WF, Xu Y, Hu QL, Munroe D, Minowada J, Housman DE, Minden MD . Molecular characterization of a chromosome translocation breakpoint t(11;14)(p13;q11) from the cell line KOPT-K1 . Leukemia . 9 . 11 . 1812–1817 . November 1995 . 7475267 .
• Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH . Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1 . Proceedings of the National Academy of Sciences of the United States of America . 92 . 21 . 9585–9589 . October 1995 . 7568177 . 40846 . 10.1073/pnas.92.21.9585 . 1995PNAS...92.9585O . free .
• Sánchez-García I, Axelson H, Rabbitts TH . Functional diversity of LIM proteins: amino-terminal activation domains in the oncogenic proteins RBTN1 and RBTN2 . Oncogene . 10 . 7 . 1301–1306 . April 1995 . 7731680 .
• Wadman I, Li J, Bash RO, Forster A, Osada H, Rabbitts TH, Baer R . Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia . The EMBO Journal . 13 . 20 . 4831–4839 . October 1994 . 7957052 . 395422 . 10.1002/j.1460-2075.1994.tb06809.x .
• Valge-Archer VE, Osada H, Warren AJ, Forster A, Li J, Baer R, Rabbitts TH . The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells . Proceedings of the National Academy of Sciences of the United States of America . 91 . 18 . 8617–8621 . August 1994 . 8078932 . 44657 . 10.1073/pnas.91.18.8617 . 1994PNAS...91.8617V . free .
• Wilkinson DA, Neale GA, Mao S, Naeve CW, Goorha RM . Elf-2, a rhombotin-2 binding ets transcription factor: discovery and potential role in T cell leukemia . Leukemia . 11 . 1 . 86–96 . January 1997 . 9001422 . 10.1038/sj.leu.2400516 . free .
• Mao S, Neale GA, Goorha RM . T-cell oncogene rhombotin-2 interacts with retinoblastoma-binding protein 2 . Oncogene . 14 . 13 . 1531–1539 . April 1997 . 9129143 . 10.1038/sj.onc.1200988 . 25877540 .
• Osada H, Grutz GG, Axelson H, Forster A, Rabbitts TH . LIM-only protein Lmo2 forms a protein complex with erythroid transcription factor GATA-1 . Leukemia . 11 . Suppl 3 . 307–312 . April 1997 . 9209374 .
• Wadman IA, Osada H, Grütz GG, Agulnick AD, Westphal H, Forster A, Rabbitts TH . The LIM-only protein Lmo2 is a bridging molecule assembling an erythroid, DNA-binding complex which includes the TAL1, E47, GATA-1 and Ldb1/NLI proteins . The EMBO Journal . 16 . 11 . 3145–3157 . June 1997 . 9214632 . 1169933 . 10.1093/emboj/16.11.3145 .
• Visvader JE, Mao X, Fujiwara Y, Hahm K, Orkin SH . The LIM-domain binding protein Ldb1 and its partner LMO2 act as negative regulators of erythroid differentiation . Proceedings of the National Academy of Sciences of the United States of America . 94 . 25 . 13707–13712 . December 1997 . 9391090 . 28370 . 10.1073/pnas.94.25.13707 . free . 1997PNAS...9413707V .
• Jurata LW, Pfaff SL, Gill GN . The nuclear LIM domain interactor NLI mediates homo- and heterodimerization of LIM domain transcription factors . The Journal of Biological Chemistry . 273 . 6 . 3152–3157 . February 1998 . 9452425 . 10.1074/jbc.273.6.3152 . free .
• Kenny DA, Jurata LW, Saga Y, Gill GN . Identification and characterization of LMO4, an LMO gene with a novel pattern of expression during embryogenesis . Proceedings of the National Academy of Sciences of the United States of America . 95 . 19 . 11257–11262 . September 1998 . 9736723 . 21629 . 10.1073/pnas.95.19.11257 . free . 1998PNAS...9511257K .
• Ono Y, Fukuhara N, Yoshie O . TAL1 and LIM-only proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3 . Molecular and Cellular Biology . 18 . 12 . 6939–6950 . December 1998 . 9819382 . 109277 . 10.1128/MCB.18.12.6939 .
• Bach I, Rodriguez-Esteban C, Carrière C, Bhushan A, Krones A, Rose DW, Glass CK, Andersen B, Izpisúa Belmonte JC, Rosenfeld MG . 6 . RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex . Nature Genetics . 22 . 4 . 394–399 . August 1999 . 10431247 . 10.1038/11970 . 22326394 .
• Vitelli L, Condorelli G, Lulli V, Hoang T, Luchetti L, Croce CM, Peschle C . A pentamer transcriptional complex including tal-1 and retinoblastoma protein downmodulates c-kit expression in normal erythroblasts . Molecular and Cellular Biology . 20 . 14 . 5330–5342 . July 2000 . 10866689 . 85982 . 10.1128/MCB.20.14.5330-5342.2000 .
• Davenport J, Neale GA, Goorha R . Identification of genes potentially involved in LMO2-induced leukemogenesis . Leukemia . 14 . 11 . 1986–1996 . November 2000 . 11069036 . 10.1038/sj.leu.2401913 . 5827053 .
• Sum EY, Peng B, Yu X, Chen J, Byrne J, Lindeman GJ, Visvader JE . The LIM domain protein LMO4 interacts with the cofactor CtIP and the tumor suppressor BRCA1 and inhibits BRCA1 activity . The Journal of Biological Chemistry . 277 . 10 . 7849–7856 . March 2002 . 11751867 . 10.1074/jbc.M110603200 . free .

Notes and References

1. Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH . The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13 . Proceedings of the National Academy of Sciences of the United States of America . 88 . 10 . 4367–4371 . May 1991 . 2034676 . 51660 . 10.1073/pnas.88.10.4367 . free . 1991PNAS...88.4367B .
2. Warren AJ, Colledge WH, Carlton MB, Evans MJ, Smith AJ, Rabbitts TH . The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development . Cell . 78 . 1 . 45–57 . July 1994 . 8033210 . 10.1016/0092-8674(94)90571-1 . 7156927 .
3. Fisch P, Boehm T, Lavenir I, Larson T, Arno J, Forster A, Rabbitts TH . T-cell acute lymphoblastic lymphoma induced in transgenic mice by the RBTN1 and RBTN2 LIM-domain genes . Oncogene . 7 . 12 . 2389–2397 . December 1992 . 1461647 .
4. Abraham BJ, Hnisz D, Weintraub AS, Kwiatkowski N, Li CH, Li Z, Weichert-Leahey N, Rahman S, Liu Y, Etchin J, Li B, Shen S, Lee TI, Zhang J, Look AT, Mansour MR, Young RA . 6 . Small genomic insertions form enhancers that misregulate oncogenes . Nature Communications . 8 . 14385 . February 2017 . 28181482 . 5309821 . 10.1038/ncomms14385 . 2017NatCo...814385A .
5. Rahman S, Magnussen M, León TE, Farah N, Li Z, Abraham BJ, Alapi KZ, Mitchell RJ, Naughton T, Fielding AK, Pizzey A, Bustraan S, Allen C, Popa T, Pike-Overzet K, Garcia-Perez L, Gale RE, Linch DC, Staal FJ, Young RA, Look AT, Mansour MR . 6 . Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia . Blood . 129 . 24 . 3221–3226 . June 2017 . 28270453 . 5472898 . 10.1182/blood-2016-09-742148 .
6. Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH . Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1 . Proceedings of the National Academy of Sciences of the United States of America . 92 . 21 . 9585–9589 . October 1995 . 7568177 . 40846 . 10.1073/pnas.92.21.9585 . 1995PNAS...92.9585O . free .
7. Mao S, Neale GA, Goorha RM . T-cell oncogene rhombotin-2 interacts with retinoblastoma-binding protein 2 . Oncogene . 14 . 13 . 1531–1539 . April 1997 . 9129143 . 10.1038/sj.onc.1200988 . 25877540 .
8. Bégay-Müller V, Ansieau S, Leutz A . The LIM domain protein Lmo2 binds to AF6, a translocation partner of the MLL oncogene . FEBS Letters . 521 . 1–3 . 36–38 . June 2002 . 12067721 . 10.1016/s0014-5793(02)02814-4 . 2002FEBSL.521...36B . 29461336 .
9. Wadman I, Li J, Bash RO, Forster A, Osada H, Rabbitts TH, Baer R . Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia . The EMBO Journal . 13 . 20 . 4831–4839 . October 1994 . 7957052 . 395422 . 10.1002/j.1460-2075.1994.tb06809.x .
10. Valge-Archer VE, Osada H, Warren AJ, Forster A, Li J, Baer R, Rabbitts TH . The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells . Proceedings of the National Academy of Sciences of the United States of America . 91 . 18 . 8617–8621 . August 1994 . 8078932 . 44657 . 10.1073/pnas.91.18.8617 . 1994PNAS...91.8617V . free .
11. Goardon N, Lambert JA, Rodriguez P, Nissaire P, Herblot S, Thibault P, Dumenil D, Strouboulis J, Romeo PH, Hoang T . 6 . ETO2 coordinates cellular proliferation and differentiation during erythropoiesis . The EMBO Journal . 25 . 2 . 357–366 . January 2006 . 16407974 . 1383517 . 10.1038/sj.emboj.7600934 .