LMO2 at 25 years: A paradigm of chromosomal translocation proteins

Open Biology

Volumn 5, Issue 6, 2015, Pages

  Chambers, Jennifer ^a   Rabbitts, Terence H ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Angiogenesis; Chromosomal translocations; Haematopoiesis; Leukaemia; LMO2; X chromosome linked severe combined immuno deficiency syndrome

Indexed keywords

LIM PROTEIN; LMO2 PROTEIN, HUMAN; ONCOPROTEIN; SIGNAL TRANSDUCING ADAPTOR PROTEIN;

GENE TRANSLOCATION; GENETICS; HUMAN; PATHOLOGY; T CELL LEUKEMIA;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; HUMANS; LEUKEMIA, T-CELL; LIM DOMAIN PROTEINS; PROTO-ONCOGENE PROTEINS; TRANSLOCATION, GENETIC;

EID: 84942437038     PISSN: None     EISSN: 20462441     Source Type: Journal    
DOI: 10.1098/rsob.150062     Document Type: Review

References (131)

1. Rabbitts TH. 1991 Translocations, master genes, and differences between the origins of acute and chronic leukemias. Cell 67, 641-644. (doi:10.1016/0092-8674(91)90057-6)
2. Rabbitts TH, Boehm T. 1991 Structural and functional chimerism results from chromosomal translocation in lymphoid tumors. Adv. Immunol. 50, 119-146. (doi:10.1016/s0065-2776(08)60824-x)
3. Lefranc MP, Rabbitts TH. 1985 Two tandemly organized human genes encoding the T-cell gamma constant-region sequences show multiple rearrangement in different T-cell types. Nature 316, 464-466. (doi:10.1038/316464a0)
4. Boehm T, Foroni L, Kaneko Y, Perutz MF, Rabbitts TH. 1991 The rhombotin family of cysteinerich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. Proc. Natl Acad. Sci. USA 88, 4367-4371. (doi:10.1073/pnas.88. 10.4367)
5. Royer-Pokora B, Loos U, Ludwig WD. 1991 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, 1887-1893.
6. Boehm T, Foroni L, Kennedy M, Rabbitts TH. 1990 The rhombotin gene belongs to a class of transcriptional regulators with a potential novel protein dimerisation motif. Oncogene 5, 1103-1105.
7. Boehm T, Buluwela L, Williams D, White L, Rabbitts TH. 1988 A cluster of chromosome 11p13 translocations found via distinct D-D and D-D-J rearrangements of the human T cell receptor delta chain gene. EMBO J. 7, 2011-2017.
8. McGuire EA, Hockett RD, Pollock KM, Bartholdi MF, O'Brien SJ, Korsmeyer SJ. 1989 The t(11;14)( p15;q11) in a T-cell acute lymphoblastic leukemia cell line activates multiple transcripts, including Ttg-1, a gene encoding a potential zinc finger protein. Mol. Cell. Biol. 9, 2124-2132.
9. Hacein-Bey-Abina S et al. 2003 LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302, 415-419. (doi:10.1126/science.1088547)
10. Howe SJ et al. 2008 Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. J. Clin. Invest. 118, 3143-3150. (doi:10. 1172/JCI35798)
11. Hacein-Bey-Abina S et al. 2008 Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 118, 3132-3142. (doi:10.1172/JCI35700)
12. Royer-Pokora B, Rogers M, Zhu TH, Schneider S, Loos U, Bolitz U. 1995 The TTG-2/RBTN2 T cell oncogene encodes two alternative transcripts from two promoters: the distal promoter is removed by most 11p13 translocations in acute T cell leukaemia's (T-ALL). Oncogene 10, 1353-1360.
13. Oram SH et al. 2010 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. Oncogene 29, 5796-5808. (doi:10.1038/onc.2010.320)
14. Pettersen EF et al. 2004 UCSF Chimera - a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605-1612. (doi:10. 1002/jcc.20084)
15. El Omari K, Hoosdally SJ, Tuladhar K, Karia D, Vyas P, Patient R, Porcher C, Mancini EJ. 2011 Structure of the leukemia oncogene LMO2: implications for the assembly of a hematopoietic transcription factor complex. Blood 117, 2146-2156. (doi:10.1182/blood-2010-07-293357)
16. McCormack MP, Rabbitts TH. 2004 Activation of the T-cell oncogene LMO2 after gene therapy for X-linked severe combined immunodeficiency. N. Eng. J. Med. 350, 913-922. (doi:10.1056/NEJMra032207)
17. Foroni L et al. 1992 The rhombotin gene family encode related LIM-domain proteins whose differing expression suggests multiple roles in mouse development. J. Mol. Biol. 226, 747-761. (doi:10.1016/0022-2836(92)90630-3)
18. Grutz G, Forster A, Rabbitts TH. 1998 Identification of the LMO4 gene encoding an interaction partner of the LIM-binding protein LDB1/NLI1: a candidate for displacement by LMO proteins in T cell acute leukaemia. Oncogene 17, 2799-2803. (doi:10. 1038/sj.onc.1202502)
19. Matthews JM, Lester K, Joseph S, Curtis DJ. 2013 LIM-domain-only proteins in cancer. Nat. Rev. Cancer 13, 111-122. (doi:10.1038/nrc3418)
20. Kenny DA, Jurata LW, Saga Y, Gill GN. 1998 Identification and characterization of LMO4, an LMO gene with a novel pattern of expression during embryogenesis. Proc. Natl Acad. Sci. USA 95, 11 257-11 262. (doi:10.1073/pnas.95.19.11257)
21. Way JC, Chalfie M. 1988 mec-3, a homeoboxcontaining gene that specifies differentiation of the touch receptor neurons in C. elegans. Cell 54, 5-16. (doi:10.1016/0092-8674(88)90174-2)
22. Karlsson O, Thor S, Norberg T, Ohlsson H, Edlund T. 1990 Insulin gene enhancer binding protein Isl-1 is a member of a novel class of proteins containing both a homeo-and a Cys-His domain. Nature 344, 879-882. (doi:10.1038/344879a0)
23. Freyd G, Kim SK, Horvitz HR. 1990 Novel cysteinerich motif and homeodomain in the product of the Caenorhabditis elegans cell lineage gene lin-11. Nature 344, 876-879. (doi:10.1038/344876a0)
24. Warren AJ, Colledge WH, Carlton MB, Evans MJ, Smith AJ, Rabbitts TH. 1994 The oncogenic cysteinerich LIM domain protein rbtn2 is essential for erythroid development. Cell 78, 45-57. (doi:10. 1016/0092-8674(94)90571-1)
25. Tse E et al. 2004 Null mutation of the Lmo4 gene or a combined null mutation of the Lmo1/Lmo3 genes causes perinatal lethality, and Lmo4 controls neural tube development in mice. Mol. Cell. Biol. 24, 2063-2073. (doi:10.1128/MCB.24.5.2063-2073. 2004)
26. Cleary ML. 1991 Oncogenic conversion of transcription factors by chromosomal translocations. Cell 66, 619-622. (doi:10.1016/0092-8674(91)90105-8)
27. Boehm T, Greenberg JM, Buluwela L, Lavenir I, Forster A, Rabbitts TH. 1990 An unusual structure of a putative T cell oncogene which allows production of similar proteins from distinct mRNAs. EMBO J. 9, 857-868.
28. Boehm T, Spillantini MG, Sofroniew MV, Surani MA, Rabbitts TH. 1991 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, 695-703.
29. Neale GA, Mao S, Parham DM, Murti KG, Goorha RM. 1995 Expression of the proto-oncogene rhombotin-2 is identical to the acute phase response protein metallothionein, suggesting multiple functions. Cell Growth Diff. 6, 587-596.
30. McCormack MP, Forster A, Drynan L, Pannell R, Rabbitts TH. 2003 The LMO2 T-cell oncogene is activated via chromosomal translocations or retroviral insertion during gene therapy but has no mandatory role in normal T-cell development. Mol. Cell. Biol. 23, 9003-9013. (doi:10.1128/MCB.23.24. 9003-9013.2003)
31. Van Vlierberghe P et al. 2006 The cryptic chromosomal deletion del(11)( p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. Blood 108, 3520-3529. (doi:10.1182/blood-2006-04-019927)
32. Wu L et al. 2015 High frequency of cryptic chromosomal rearrangements involving the LMO2 gene in T-cell acute lymphoblastic leukemia. Haematologica 100, e233-e236. (doi:10.3324/haematol.2014.120089)
33. Ferrando AA et al. 2002 Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 1, 75-87. (doi:10.1016/S1535-6108(02)00018-1)
34. Begley CG et al. 1989 Chromosomal translocation in a human leukemic stem-cell line disrupts the T-cell antigen receptor delta-chain diversity region and results in a previously unreported fusion transcript. Proc. Natl Acad. Sci. USA 86, 2031-2035. (doi:10. 1073/pnas.86.6.2031)
35. Finger LR, Kagan J, Christopher G, Kurtzberg J, Hershfield MS, Nowell PC, Croce CM. 1989 Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma. Proc. Natl Acad. Sci. USA 86, 5039-5043. (doi:10. 1073/pnas.86.13.5039)
36. Schatz DG, Ji Y. 2011 Recombination centres and the orchestration of V(D)J recombination. Nat. Rev. Immunol. 11, 251-263. (doi:10.1038/nri2941)
37. Garcia IS et al. 1991 A study of chromosome 11p13 translocations involving TCR beta and TCR delta in human T cell leukaemia. Oncogene 6, 577-582.
38. Hacein-Bey-Abina S et al. 2003 A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Eng. J. Med. 348, 255-256. (doi:10.1056/NEJM2003011634 80314)
39. Hacein-Bey-Abina S et al. 2002 Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N. Eng. J. Med. 346, 1185-1193. (doi:10.1056/NEJMoa012616)
40. Archer VE, Breton J, Sanchez-Garcia I, Osada H, Forster A, Thomson AJ, Rabbitts TH. 1994 Cysteinerich LIM domains of LIM-homeodomain and LIM-only proteins contain zinc but not iron. Proc. Natl Acad. Sci. USA 91, 316-320. (doi:10.1073/pnas.91.1.316)
41. Perez-Alvarado GC, Kosa JL, Louis HA, Beckerle MC, Winge DR, Summers MF. 1996 Structure of the cysteine-rich intestinal protein, CRIP. J. Mol. Biol. 257, 153-174. (doi:10.1006/jmbi.1996.0153)
42. Sadler I, Crawford AW, Michelsen JW, Beckerle MC. 1992 Zyxin and cCRP: two interactive LIM domain proteins associated with the cytoskeleton. J. Cell Biol. 119, 1573-1587. (doi:10.1083/jcb.119.6.1573)
43. Valge-Archer VE, Osada H, Warren AJ, Forster A, Li J, Baer R, Rabbitts TH. 1994 The LIM protein RBTN2 and the basic helix-loop-helix protein TAL1 are present in a complex in erythroid cells. Proc. Natl Acad. Sci. USA 91, 8617-8621. (doi:10.1073/pnas. 91.18.8617)
44. Schmeichel KL, Beckerle MC. 1994 The LIM domain is a modular protein-binding interface. Cell 79, 211-219. (doi:10.1016/0092-8674(94)90191-0)
45. Wadman IA et al. 1997 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. EMBO J. 16, 3145-3157. (doi:10.1093/emboj/16.11.3145)
46. Schmeichel KL, Beckerle MC. 1997 Molecular dissection of a LIM domain. Mol. Biol. Cell 8, 219-230. (doi:10.1091/mbc.8.2.219)
47. Wadman I et al. 1994 Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. EMBO J. 13, 4831-4839.
48. Grutz GG, Bucher K, Lavenir I, Larson T, Larson R, Rabbitts TH. 1998 The oncogenic T cell LIM-protein Lmo2 forms part of a DNA-binding complex specifically in immature T cells. EMBO J. 17, 4594-4605. (doi:10.1093/emboj/17.16.4594)
49. Sewell H, Tanaka T, El Omari K, Mancini EJ, Cruz A, Fernandez-Fuentes N, Chambers J, Rabbitts TH. 2014 Conformational flexibility of the oncogenic protein LMO2 primes the formation of the multiprotein transcription complex. Sci. Rep. 4, 3643. (doi:10.1038/srep03643)
50. Appert A et al. 2009 Targeting LMO2 with a peptide aptamer establishes a necessary function in overt T-cell neoplasia. Cancer Res. 69, 4784-4790. (doi:10.1158/0008-5472.CAN-08-4774)
51. Lecuyer E, Lariviere S, Sincennes MC, Haman A, Lahlil R, Todorova M, Tremblay M, Wilkes BC, Hoang T. 2007 Protein stability and transcription factor complex assembly determined by the SCL-LMO2 interaction. J. Biol. Chem. 282, 33 649-33 658. (doi:10.1074/jbc.M703939200)
52. Baer R. 1993 TAL1, TAL2 and LYL1: a family of basic helix-loop-helix proteins implicated in T cell acute leukaemia. Semin. Cancer Biol. 4, 341-347.
53. Larson RC et al. 1996 Protein dimerization between Lmo2 (Rbtn2) and Tal1 alters thymocyte development and potentiates T cell tumorigenesis in transgenic mice. EMBO J. 15, 1021-1027.
54. Ono Y, Fukuhara N, Yoshie O. 1997 Transcriptional activity of TAL1 in T cell acute lymphoblastic leukemia (T-ALL) requires RBTN1 or-2 and induces TALLA1, a highly specific tumor marker of T-ALL. J. Biol. Chem. 272, 4576-4581. (doi:10.1074/jbc. 272.7.4576)
55. Osada H, Grutz G, Axelson H, Forster A, Rabbitts TH. 1995 Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. Proc. Natl Acad. Sci. USA 92, 9585-9589. (doi:10.1073/pnas.92.21.9585)
56. Ono Y, Fukuhara N, Yoshie O. 1998 TAL1 and LIMonly proteins synergistically induce retinaldehyde dehydrogenase 2 expression in T-cell acute lymphoblastic leukemia by acting as cofactors for GATA3. Mol. Cell. Biol. 18, 6939-6950.
57. Agulnick AD, Taira M, Breen JJ, Tanaka T, Dawid IB, Westphal H. 1996 Interactions of the LIM-domainbinding factor Ldb1 with LIM homeodomain proteins. Nature 384, 270-272. (doi:10.1038/384270a0)
58. Vitelli L, Condorelli G, Lulli V, Hoang T, Luchetti L, Croce CM, Peschle C. 2000 A pentamer transcriptional complex including tal-1 and retinoblastoma protein downmodulates c-kit expression in normal erythroblasts. Mol. Cell. Biol. 20, 5330-5342. (doi:10.1128/MCB.20.14.5330-5342.2000)
59. Anderson KP, Crable SC, Lingrel JB. 1998 Multiple proteins binding to a GATA-E box-GATA motif regulate the erythroid Kruppel-like factor (eKLF) gene. J. Biol. Chem. 273, 14 347-14 354. (doi:10. 1074/jbc.273.23.14347)
60. Deane JE, Sum E, Mackay JP, Lindeman GJ, Visvader JE, Matthews JM. 2001 Design, production and characterization of FLIN2 and FLIN4: the engineering of intramolecular ldb1:LMO complexes. Protein Eng. 14, 493-499. (doi:10.1093/protein/14. 7.493)
61. Ryan DP et al. 2006 Identification of the key LMO2-binding determinants on LDB1. J. Mol. Biol. 359, 66-75. (doi:10.1016/j.jmb.2006.02.074)
62. Matthews JM, Visvader JE, Mackay JP. 2001 1H, 15N and 13C assignments of FLIN2, an intramolecular LMO2:LDB1 complex. J. Biomol. NMR 21, 385-386. (doi:10.1023/A:1013373203772)
63. El Omari K, Porcher C, Mancini EJ. 2010 Purification, crystallization and preliminary X-ray analysis of a fusion of the LIM domains of LMO2 and the LID domain of LDB1. Acta Crystallogr. Sec. F Struct. Biol. Crystal. Commun. 66, 1466-1469. (doi:10.1107/S1744309110032872)
64. El Omari K et al. 2013 Structural basis for LMO2-driven recruitment of the SCL:E47bHLH heterodimer to hematopoietic-specific transcriptional targets. Cell Rep. 4, 135-147. (doi:10.1016/j.celrep.2013. 06.008)
65. Rossant J, Bernelot-Moens C, Nagy A. 1993 Genome manipulation in embryonic stem cells. Phil. Trans. R. Soc. Lond. B 339, 207-215. (doi:10.1098/rstb.1993.0018)
66. Yamada Y, Warren AJ, Dobson C, Forster A, Pannell R, Rabbitts TH. 1998 The T cell leukemia LIM protein Lmo2 is necessary for adult mouse hematopoiesis. Proc. Natl Acad. Sci. USA 95, 3890-3895. (doi:10.1073/pnas.95.7.3890)
67. Yamada Y, Pannell R, Forster A, Rabbitts TH. 2000 The oncogenic LIM-only transcription factor Lmo2 regulates angiogenesis but not vasculogenesis in mice. Proc. Natl Acad. Sci. USA 97, 320-324. (doi:10.1073/pnas.97.1.320)
68. Yamada Y, Pannell R, Forster A, Rabbitts TH. 2002 The LIM-domain protein Lmo2 is a key regulator of tumour angiogenesis: a new anti-angiogenesis drug target. Oncogene 21, 1309-1315. (doi:10.1038/sj. onc.1205285)
69. Shivdasani RA, Mayer EL, Orkin SH. 1995 Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373, 432-434. (doi:10.1038/373432a0)
70. Robb L, Lyons I, Li R, Hartley L, Kontgen F, Harvey RP, Metcalf D, Begley CG. 1995 Absence of yolk sac hematopoiesis from mice with a targeted disruption of the scl gene. Proc. Natl Acad. Sci. USA 92, 7075-7079. (doi:10.1073/pnas.92.15.7075)
71. Pevny L, Simon MC, Robertson E, Klein WH, Tsai SF, D'Agati V, Orkin SH, Costantini F. 1991 Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 349, 257-260. (doi:10.1038/349257a0)
72. Simon MC, Pevny L, Wiles MV, Keller G, Costantini F, Orkin SH. 1992 Rescue of erythroid development in gene targeted GATA-1-mouse embryonic stem cells. Nat. Genet. 1, 92-98. (doi:10.1038/ng0592-92)
73. Tsai FY et al. 1994 An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371, 221-226. (doi:10.1038/371221a0)
74. Durand C, Dzierzak E. 2005 Embryonic beginnings of adult hematopoietic stem cells. Haematologica 90, 100-108.
75. Medvinsky A, Rybtsov S, Taoudi S. 2011 Embryonic origin of the adult hematopoietic system: advances and questions. Development 138, 1017-1031. (doi:10.1242/dev.040998)
76. Visvader JE, Mao X, Fujiwara Y, Hahm K, Orkin SH. 1997 The LIM-domain binding protein LDB1 and its partner LMO2 act as negative regulators of erythroid differentiation. Proc. Natl Acad. Sci. USA 94, 13 707-13 712. (doi:10.1073/pnas.94.25.13707)
77. Silver L, Palis J. 1997 Initiation of murine embryonic erythropoiesis: a spatial analysis. Blood 89, 1154-1164.
78. Manaia A et al. 2000 Lmo2 and GATA-3 associated expression in intraembryonic hemogenic sites. Development 127, 643-653.
79. Lacaud G, Keller G, Kouskoff V. 2004 Tracking mesoderm formation and specification to the hemangioblast in vitro. Trends Cardiovasc. Med. 14, 314-317. (doi:10.1016/j.tcm.2004.09.004)
80. Coma S, Allard-Ratick M, Akino T, van Meeteren LA, Mammoto A, Klagsbrun M. 2013 GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2. Angiogenesis 16, 939-952. (doi:10.1007/s10456-013-9370-9)
81. Lee SK et al. 2003 Identification of novel antiangiogenic factors by in silico functional gene screening method. J. Biotechnol. 105, 51-60. (doi:10.1016/S0168-1656(03)00183-4)
82. Hinks GL et al. 1997 Expression of LIM protein genes Lmo1, Lmo2, and Lmo3 in adult mouse hippocampus and other forebrain regions: differential regulation by seizure activity. J. Neurosci. 17, 5549-5559.
83. Han C et al. 2005 Human Bex2 interacts with LMO2 and regulates the transcriptional activity of a novel DNA-binding complex. Nucleic Acids Res. 33, 6555-6565. (doi:10.1093/nar/gki964)
84. Kim SH et al. In press. The LIM-only transcription factor LMO2 determines tumorigenic and angiogenic traits in glioma stem cells. Cell Death Diff. (doi:10.1038/cdd.2015.7)
85. Akashi K et al. 2003 Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. Blood 101, 383-389. (doi:10.1182/blood-2002-06-1780)
86. Fisch P et al. 1992 T-cell acute lymphoblastic lymphoma induced in transgenic mice by the RBTN1 and RBTN2 LIM-domain genes. Oncogene 7, 2389-2397.
87. Larson RC et al. 1994T cell tumours of disparate phenotype in mice transgenic for Rbtn-2. Oncogene 9, 3675-3681.
88. Cleveland SM et al. 2013 Lmo2 induces hematopoietic stem cell-like features in T-cell progenitor cells prior to leukemia. Stem Cells 31, 882-894. (doi:10.1002/stem.1345)
89. Larson RC, Osada H, Larson TA, Lavenir I, Rabbitts TH. 1995 The oncogenic LIM protein Rbtn2 causes thymic developmental aberrations that precede malignancy in transgenic mice. Oncogene 11, 853-862.
90. McCormack MP, Young LF, Vasudevan S, de Graaf CA, Codrington R, Rabbitts TH, Jane SM, Curtis DJ. 2010 The Lmo2 oncogene initiates leukemia in mice by inducing thymocyte selfrenewal. Science 327, 879-883. (doi:10.1126/science.1182378)
91. Takahashi K, Yamanaka S. 2006 Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676. (doi:10.1016/j.cell.2006.07.024)
92. Vereide DT, Vickerman V, Swanson SA, Chu LF, McIntosh BE, Thomson JA. 2014 An expandable, inducible hemangioblast state regulated by fibroblast growth factor. Stem Cell Rep. 3, 1043-1057. (doi:10.1016/j.stemcr.2014.10.003)
93. Batta K, Florkowska M, Kouskoff V, Lacaud G. 2014 Direct reprogramming of murine fibroblasts to hematopoietic progenitor cells. Cell Rep. 9, 1871-1884. (doi:10.1016/j.celrep.2014.11.002)
94. Riddell J et al. 2014 Reprogramming committed murine blood cells to induced hematopoietic stem cells with defined factors. Cell 157, 549-564. (doi:10.1016/j.cell.2014.04.006)
95. Yamanaka S. 2009 A fresh look at iPS cells. Cell 137, 13-17. (doi:10.1016/j.cell.2009.03.034)
96. Neale GA, Rehg JE, Goorha RM. 1995 Ectopic expression of rhombotin-2 causes selective expansion of CD4-CD8-lymphocytes in the thymus and T-cell tumors in transgenic mice. Blood 86, 3060-3071.
97. Zhou H et al. 2009 Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4, 381-384. (doi:10.1016/j.stem. 2009.04.005)
98. Greenberg JM et al. 1990 Segmental and developmental regulation of a presumptive T-cell oncogene in the central nervous system. Nature 344, 158-160. (doi:10.1038/344158a0)
99. Nam CH, Lobato MN, Appert A, Drynan LF, Tanaka T, Rabbitts TH. 2008 An antibody inhibitor of the LMO2-protein complex blocks its normal and tumorigenic functions. Oncogene 27, 4962-4968. (doi:10.1038/onc.2008.130)
100. Tanaka T, Sewell H, Waters S, Phillips SE, Rabbitts TH. 2011 Single domain intracellular antibodies from diverse libraries: emphasizing dual functions of LMO2 protein interactions using a single VH domain. J. Biol. Chem. 286, 3707-3716. (doi:10. 1074/jbc.M110.188193)
101. Herblot S, Steff AM, Hugo P, Aplan PD, Hoang T. 2000 SCL and LMO1 alter thymocyte differentiation: inhibition of E2A-HEB function and pre-T alpha chain expression. Nat. Immunol. 1, 138-144. (doi:10.1038/77819)
102. Gutierrez A, Look AT. 2007 NOTCH and PI3K-AKT pathways intertwined. Cancer Cell 12, 411-413. (doi:10.1016/j.ccr.2007.10.027)
103. Robb L, Rasko JE, Bath ML, Strasser A, Begley CG. 1995 scl, a gene frequently activated in human T cell leukaemia, does not induce lymphomas in transgenic mice. Oncogene 10, 205-209.
104. Pike-Overzet K, van der Burg M, Wagemaker G, van Dongen JJ, Staal FJ. 2007 New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol. Therapy 15, 1910-1916. (doi:10.1038/sj.mt.6300297)
105. Staal FJ, Pike-Overzet K, Ng YY, van Dongen JJ. 2008 Sola dosis facit venenum. Leukemia in gene therapy trials: a question of vectors, inserts and dosage? Leukemia 22, 1849-1852. (doi:10.1038/leu.2008.219)
106. Coustan-Smith E et al. 2009 Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 10, 147-156. (doi:10.1016/S1470-2045(08)70314-0)
107. Zhang J et al. 2012 The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157-163. (doi:10.1038/nature10725)
108. McCormack MP et al. 2013 Requirement for Lyl1 in a model of Lmo2-driven early T-cell precursor ALL. Blood 122, 2093-2103. (doi:10.1182/blood-2012-09-458570)
109. Shields BJ, Alserihi R, Nasa C, Bogue C, Alexander WS, McCormack MP. 2014 Hhex regulates Kit to promote radioresistance of self-renewing thymocytes in Lmo2-transgenic mice. Leukemia 29, 927-938. (doi:10.1038/leu.2014.292)
110. Martins VC et al. 2014 Cell competition is a tumour suppressor mechanism in the thymus. Nature 509, 465-470. (doi:10.1038/nature13317)
111. Wilkinson-White L, Matthews JM. 2014 The PA207 peptide inhibitor of LIM-only protein 2 (Lmo2) targets Zinc Finger domains in a non-specific manner. Protein Pept. Lett. 21, 132-139. (doi:10. 2174/09298665113206660116)
112. Natkunam Y et al. 2007 The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas. Blood 109, 1636-1642. (doi:10.1182/blood-2006-08-039024)
113. Deucher AM, Qi Z, Yu J, George TI, Etzell JE. 2015 BCL6 expression correlates with the t(1;19) translocation in B-lymphoblastic leukemia. Am. J. Clin. Pathol. 143, 547-557. (doi:10.1309/AJCPO4U4VYAAOTEL)
114. de Boer J, Yeung J, Ellu J, Ramanujachar R, Bornhauser B, Solarska O, Hubank M, Williams O, Brady HJM. 2011 The E2A-HLF oncogenic fusion protein acts through Lmo2 and Bcl-2 to immortalize hematopoietic progenitors. Leukemia 25, 321-330. (doi:10.1038/leu.2010.253)
115. Malumbres R et al. 2011 LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome. Haematologica 96, 980-986. (doi:10.3324/haematol.2011.040568)
116. Cubedo E et al. 2012 Identification of LMO2 transcriptome and interactome in diffuse large B-cell lymphoma. Blood 119, 5478-5491. (doi:10. 1182/blood-2012-01-403154)
117. Natkunam Y et al. 2008 LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. J. Clin. Oncol. 26, 447-454. (doi:10.1200/JCO.2007.13. 0690)
118. Lossos IS et al. 2004 Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N. Eng. J. Med. 350, 1828-1837. (doi:10. 1056/NEJMoa032520)
119. Nakata K et al. 2009 LMO2 is a novel predictive marker for a better prognosis in pancreatic cancer. Neoplasia 11, 712-719. (doi:10.1593/neo. 09418)
120. Gratzinger D et al. 2009 The transcription factor LMO2 is a robust marker of vascular endothelium and vascular neoplasms and selected other entities. Am. J. Clin. Pathol. 131, 264-278. (doi:10.1309/AJCP5FP3NAXAXRJE)
121. Pui CH, Relling MV, Downing JR. 2004 Acute lymphoblastic leukemia. N. Eng. J. Med. 350, 1535-1548. (doi:10.1056/NEJMra023001)
122. Pui CH, Evans WE. 1998 Acute lymphoblastic leukemia. N. Eng. J. Med. 339, 605-615. (doi:10. 1056/NEJM199808273390907)
123. Carmeliet P. 2003 Angiogenesis in health and disease. Nat. Med. 9, 653-660. (doi:10.1038/nm0603-653)
124. Wells JA, McClendon CL. 2007 Reaching for highhanging fruit in drug discovery at protein-protein interfaces. Nature 450, 1001-1009. (doi:10.1038/nature06526)
125. Yuan JY, Wang F, Yu J, Yang GH, Liu XL, Zhang JW. 2009 MicroRNA-223 reversibly regulates erythroid and megakaryocytic differentiation of K562 cells. J. Cell. Mol. Med. 13, 4551-4559. (doi:10.1111/j. 1582-4934.2008.00585.x)
126. Zhang J, Rabbitts TH. 2014 Intracellular antibody capture: a molecular biology approach to inhibitors of protein-protein interactions. Biochim. Biophys. Acta 1844, 1970-1976. (doi:10.1016/j.bbapap. 2014.05.009)
127. Tse E, Lobato MN, Forster A, Tanaka T, Chung GT, Rabbitts TH. 2002 Intracellular antibody capture technology: application to selection of intracellular antibodies recognising the BCR-ABL oncogenic protein. J. Mol. Biol. 317, 85-94. (doi:10.1006/jmbi.2002.5403)
128. Tanaka T, Rabbitts TH. 2012 Intracellular antibody capture (IAC) methods for single domain antibodies. Methods Mol. Biol. 911, 151-173. (doi:10.1007/978-1-61779-968-6-10)
129. Tanaka T, Rabbitts TH. 2010 Protocol for the selection of single-domain antibody fragments by third generation intracellular antibody capture. Nat. Protoc. 5, 67-92. (doi:10.1038/nprot.2009. 199)
130. Visintin M, Tse E, Axelson H, Rabbitts TH, Cattaneo A. 1999 Selection of antibodies for intracellular function using a two-hybrid in vivo system. Proc. Natl Acad. Sci. USA 96, 11 723-11 728. (doi:10. 1073/pnas.96.21.11723)
131. Tse E, Rabbitts TH. 2000 Intracellular antibodycaspase-mediated cell killing: an approach for application in cancer therapy. Proc. Natl Acad. Sci. USA 97, 12 266-12 271. (doi:10.1073/pnas.97.22. 12266)