The RUNX genes: Gain or loss of function in cancer

Nature Reviews Cancer

Volumn 5, Issue 5, 2005, Pages 376-387

  Blyth, Karen ^a   Cameron, Ewan R ^a   Neil, James C ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CORE BINDING FACTOR; PROTEIN CORE BINDING FACTOR BETA COFACTOR; TRANSCRIPTION FACTOR RUNX1; TRANSCRIPTION FACTOR RUNX2; TRANSCRIPTION FACTOR RUNX3; TRANSFORMING GROWTH FACTOR BETA; UNCLASSIFIED DRUG;

ACUTE GRANULOCYTIC LEUKEMIA; ACUTE LYMPHOCYTIC LEUKEMIA; B CELL LEUKEMIA; BONE DEVELOPMENT; BONE METASTASIS; CANCER; CARCINOGENESIS; CARCINOMA; CELL DIFFERENTIATION; CELL GROWTH; CELL SURVIVAL; CHROMOSOME TRANSLOCATION; DNA BINDING; DNA METHYLATION; GENE AMPLIFICATION; GENE DISRUPTION; GENE EXPRESSION; GENE FUNCTION; GENE STRUCTURE; GENETIC ANALYSIS; GENETIC PREDISPOSITION; HEMATOPOIESIS; HUMAN; HYPERPLASIA; LEUKEMIA; NERVOUS SYSTEM DEVELOPMENT; NONHUMAN; ONCOGENE; POINT MUTATION; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; RUNX GENE; T CELL LYMPHOMA; TRANSCRIPTION REGULATION; TUMOR SUPPRESSOR GENE;

ANIMALS; CORE BINDING FACTOR ALPHA SUBUNITS; DNA-BINDING PROTEINS; GENES, TUMOR SUPPRESSOR; HUMANS; LEUKEMIA; MICE; MICE, KNOCKOUT; MODELS, BIOLOGICAL; MUTATION; NEOPLASM PROTEINS; NEOPLASMS; ONCOGENES; TRANSCRIPTION FACTORS; TRANSCRIPTION, GENETIC; TRANSFORMING GROWTH FACTOR BETA; TRANSLOCATION, GENETIC;

EID: 18344372018     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1607     Document Type: Review

References (184)

1. Van Wijnen, A. J. et al. Nomenclature for Runt-related (RUNX) proteins. Oncogene 23. 4209-4210 (2004).
2. Gergen, J. P. & Butler, B. A. Isolation of the Drosophila segmentation gene runt and analysis of its expression during embryogenesis. Genes Dev. 2, 1179-1193 (1988).
3. Strippoli, P. et al. Segmental paralogy in the human genome: a large-scale triplication on 1p, 6p, and 21q. Mamm. Genome 13, 456-462 (2002).
4. Huang, X., Peng, J. W., Speck, N. A., & Bushweller, J. H. Solution structure of core binding factor β and map of the CBF a binding site. Nature Struct. Biol. 6, 624-627 (1999).
5. Miyoshi, H. et al. Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. Nucleic Acids Res. 23, 2762-2769 (1995).
6. Levanon, D. et al. A large variety of alternatively spliced and differentially expressed mRNAs are encoded by the human acute myeloid leukemia gene AML1. DNA Cell Biol. 15, 175-185 (1996).
7. Terry, A. et al. Conservation and expression of an alternative 3′ exon of Runx2 encoding a novel proline-rich C-terminal domain. Gene 336, 115-125 (2004).
8. Zeng, C. et al. Identification of a nuclear matrix targeting signal in the leukemia and bone-related AML/CBF-α transcription factors. Proc. Natl Acad. Sci USA 94, 6746-6751 (1997).
9. Levanon, D. et al. AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization. Genomics 23, 42-432 (1994).
10. Aronson, B. D., Fisher, A. L., Blechman, K., Caudy, M. & Gergen, J. P. Groucho-dependent and-independent repression activities of Runt domain proteins. Mol. Cell. Biol. 17, 5581-5587 (1997).
11. Wang, S. et al. Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Mol. Cell. Biol. 13, 3324-3339 (1993).
12. Ogawa, E. et al. Molecular cloning and characterization of PEBP2β, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2α, Virology 194, 314-331 (1993).
13. Swantek, D. & Gergen, J. P. Ftz modulates Runtdependent activation and repression of segment-polarity gene transcription. Development 131, 2281-2290 (2004).
14. Lutterbach, B. & Hiebert, S. W. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene 245, 223-235 (2000).
15. Tanaka, T. et al. The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability. Mol. Cell. Biol. 16, 3967-3979 (1996).
16. Wee, H. J., Huang, G., Shigesada, K. & Ito, Y. Serine phosphorylaton of RUNX2 with nova potential functions as negative regulatory mechanisms. EMBO Rep. 3, 967-974 (2002).
17. Yamaguchi, Y. et al. AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. J. Biol. Chem. 279, 15630-15638 (2004).
18. Jin, Y. H. et al. Transforming growth factor-ß stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J. Biol. Chem. 279, 29409-29417 (2004).
19. Franceschi, R. T. & Xiao, G. Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J. Cell Biochem. 88, 445-454 (2003).
20. Imai, Y. et al. The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1. Mol. Cell. Bol. 24, 1033-1043 (2004).
21. Otto, F., Lubbert, M., & Stock, M. Upstream and downstream targets of RUNX proteins. J. Cell Biochem. 89, 9-18 (2003).
22. Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84 321-330 (1996).
23. Wang, Q. et al. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc. Natl Acad. Sci. USA 93, 3444-3449 (1996). References 22 and 23 demonstrated that Runx1 is essential for development of the haematopoietic lineages and provided the first evidence that RUNX genes could operate as master regulators of lineage specification in mammals.
24. Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765-771 (1997).
25. Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755-764 (1997).
26. Levanon, O. et al. The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J. 21, 3454-3463 (2002).
27. Inoue, K. et al. Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Nature Neurosci 5, 946-954 (2002).
28. Mundlos, S. et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773-779 (1997).
29. Song, W. J. et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genet. 23, 166-175 (1999). Provided genetic evidence that RUNX1 can act as a tumour-suppressor gene in the myeloid lineage and that reduced function can predispose to leukaemia. Moreover, this report demonstrated that RUNX1 has an important role in megakaryocyte differentiation and function.
30. Javed, A. et al. runt homology domain transcription factors (Runx, Cbfa, and AML) mediate repression of the bone sialoprotein promoter: evidence for promoter context-dependent activity of Cbfa proteins. Mol. Cell. Biol. 21 2891-2905 (2001).
31. Goyama, S. et al. The transcriptionally active form of AML1 is required for hematopoiettc rescue of the AML1-deficient embryonic para-aortic splanchnopleural (P-Sp) region. Blood 104, 3558-3564 (2004).
32. Miyoshi, H. et al. t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc. Natl Acad Sci. USA 88, 10431-10434 (1991).
33. Slovak, M. L. et al. 21q22 balanced chromosome aberrations in therapy-related hematopoietic disorders: report from an international workshop. Genes Chromosom. Cancer 33, 379-394 (2002).
34. Roulston, D. et al. CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. Blood 92, 2879-2885 (1998).
35. Gamou, T. et al. The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood 91, 4028-4037 (1998).
36. Golub, T. R. et al. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc. Natl Acad. Sci. USA 92, 4917-4921 (1995).
37. Shurtleff, S. A. et al. TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia 9, 1985-1989 (1995).
38. Romana, S. P. et al. High frequency of t(12;21) in childhood B-lineage acute lymphoblastic leukemia. Blood 86, 4263-4269 (1995).
39. Fears, S. et al. Correlation between the ETV6/CBFA2 (TEL/ AML1] fusion gene and karyotypic abnormalities in children with B-cel precursor acute lymphoblastic leukemia. Genes Chromosom. Cancer 17, 127-135 (1996).
40. Meyers, S., Lenny, N. & Hiebert, S. W. The t(8;21) fusion protein interferes with AML-1 B-dependent transcriptional activation. Mol. Cell. Biol. 15, 1974-1982 (1995). Demonstrated that the translocation fusion product RUNX1-ETO could antagonize the transactivation function of the wild-type gene, providing evidence of a dominant-negative function in leukaemogenesis.
41. Tanaka, T. et al. Dual functions of the AML1/Evi-1 chimeric protein in the mechanism of leukemogenesis in t(3;21) leukemias. Mol. Cell. Biol. 15, 2383-2392 (1995).
42. Gelmetti, V. et al. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol. Cell. Biol. 18, 7185-7191 (1998).
43. Lutterbach, B. et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol. Cell. Biol. 18, 7176-7184 (1998).
44. Hiebert, S. W. et al. The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription, Mol. Cell. Biol. 16, 1349-1355 (1996).
45. Guidez, F. et al. Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. Blood 96, 2557-2561 (2000).
46. Tanaka, K. et al. The AML1/ETO(MTG8) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2β(CBFβ) in the nucleus more efficiently than wildtype AML1. Blood 91, 1688-1699 (1998).
47. Adya, N., Stacy, T., Speck, N. A. & Liu, P. P. The leukemic protein core binding factor β(CBFβ)-smooth-muscle myosin heavy chain sequesters CBFα2 into cytoskeletal filaments and aggregates. Mol. Cell. Biol. 18, 7432-7443 (1998).
48. Lutterbach, B., Hou, Y., Durst, K. L. & Hiebert, S. W. The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor. Proc. Natl Acad. Sci. USA 96, 12822-12827 (1999).
49. Yergeau, D. A. et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nature Genet. 15, 303-306 (1997).
50. Okuda, T. et al. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 91, 3134-3143 (1998). References 49 and 50 demonstrated the powerful effects of the RUNX1-ETO translocation product in vivo. Knock-in of RUNX1-ETO produced a very similar phenotype to loss of RUNX1, indicating that an important component of its oncogenic function in vivo is likely to be antagonism of endogenous RUNX1.
51. Castilla, L. H. et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell 87, 687-696 (1996).
52. Speck, N. A. & Gilliland, D. G. Core-binding factors in haematopoiesis and leukaemia. Nature Rev. Cancer 2, 502-513 (2002).
53. Mulloy, J. C. et al. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood 99, 15-23 (2002). Showed that expression of RUNX1-ETO in human haematopoietic stem cells greatly increases their lifespan in vitro, demonstrating that this translocation product can alter the self-renewing capacity of these cells.
54. Tonks, A. et al. The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells. Blood 101, 624-632 (2003).
55. Fenske, T., S. et al. Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice. Proc. Natl Acad. Sci. USA 101, 15184-15189 (2004).
56. de Guzman, C. G. et al. Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation. Mol. Cell. Biol. 22, 5506-5517 (2002).
57. Morrow, M., Horton, S., Kioussis, D., Brady, H. J. & Williams, O. TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity. Blood 103, 3890-3896 (2004).
58. Tsuzuki, S., Seto, M., Greaves, M. & Enver, T. Modeling first-hit functions of the t(12;21) TEL-AML1 translocation in mice. Proc. Natl Acad. Sci. USA 101, 8443-8448 (2004). References 57 and 58 described the first model systems for investigation of the preneoplastic changes associated with TEL-RUNX1 expression and offered insight into the manner in which this translocation product affects lymphoid differentiation and self-renewal in vitro and in vivo.
59. Cuenco, G. M., Nucifora, G. & Ren, R. Human AML1/ MDS1/EVI1 fusion protein induces an acute myelogenous leukemia (AML) in mice: a model for human AML. Proc. Natl Acad. Sci. USA 97, 1760-1765 (2000).
60. Osato, M. et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias. Blood 93, 1817-1824 (1999). Showed that mutations in the Runt domain of RUNX1 are associated with myeloid leukaemia and demonstrated that complete loss of function might predispose to leukaemia arising from very early myeloid cells.
61. Preudhomme, C. et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2αB gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 96, 2862-2869 (2000).
62. Harada, H., Harada, Y., Tanaka, H., Kimura, A. & Inaba, T. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood 101, 673-680 (2003).
63. Christiansen, D. H., Andersen, M. K. & Pedersen-Bjergaard, J. Mutations of AML1 are common in therapy-related myelodysplasia following therapy with alkylating agents and are significantly associated with deletion or loss of chromosome arm 7q and with subsequent leukemic transformation. Blood 104, 1474-1481 (2004).
64. Harada, H. et al. High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 103, 2316-2324 (2004).
65. Tahirov, T. H. et al. Structural analyses of DNA recognition by the AML1/Runx-1 Runt domain and its allosteric control by CBFβ. Cell 104, 755-767 (2001).
66. Carnicer, M. J. et al. AML-1 mutations outside the RUNT domain: description of two cases in myeloid malignancies. Leukemia 16, 2329-2332 (2002).
67. Imai, Y. et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Bood 96, 3154-3160 (2000).
68. Michaud, J. et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 99, 1364-1372 (2002).
69. Ichikawa, M. et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nature Med. 10, 299-304 (2004). First paper to describe conditional tissue-specific knockout of Runx1. This model identifies a range of haematopoietic lineages that are dependent on Runx1 integrity for their differentiation and function and showed that loss of Runx1 alone causes expansion of haematopoietic stem cells.
70. Li, Q. L. et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109, 113-124 (2002). Showed that loss of Runx3 resulted in gastric epithelial hyperplasia and loss of sensitivity to the growth-inhibitory effects of TGFβ. It also provided the first evidence that RUNX3 might operate as a tumour-suppressor gene in human gastric cancer. Note that an alternative explanation for the epithelial hyperplasia is proposed in reference 78, where it is suggested that the epithelial changes are secondary to chronic immune-mediated inflammation.
71. Goel, A. et al. Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. Int. J. Cancer 112, 754-759 (2004).
72. Kim, T. Y. et al. Methylation of RUNX3 in various types of human cancers and premalignant stages of gastric carcinoma. Lab. Invest. 84, 479-484 (2004).
73. Ku, J. L. et al. Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Oncogene 23, 6736-6742 (2004).
74. Li, Q. L. et al. Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer. Biochem. Biophys. Res. Commun. 314, 223-228 (2004).
75. Xiao, W. H. & Liu, W. W. Hemizygous deletion and hypermethylation of RUNX3 gene in hepatocellular carcinoma. World J. Gastroenterol. 10, 376-380 (2004).
76. Sakakura, C. et al. Frequent downregufetion of the runt domain transcription factors RUNX1, RUNX3 and their cofactor CBFB in gastric cancer. Int. J. Cancer 113, 221-228 (2005).
77. Bestor, T. H. Unanswered questions about the role of promoter methylation in carcinogenesis. Ann. NY Acad. Sci. 983, 22-27 (2003).
78. Brenner, O. et al. Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proc. Natl Acad. Sci. USA 101, 16016-16021 (2004).
79. Ito, Y. & Miyazono, K. RUNX transcription factors as key targets of TGF-β superfamily signaling. Curr. Opin. Genet. Dev. 13, 43-47 (2003).
80. Guo, W. H. et al. Inhibition of growth of mouse gastric cancer cells by Runx3, a novel tumor suppressor. Oncogene 21, 8351-8355 (2002).
81. Torquati, A. et al. RUNXS inhibits cell proliferation and induces apoptosis by reinstating transforming growth factor β responsiveness in esophageal adenocarcinoma cells. Surgery 136, 310-316 (2004).
82. Greaves, M. F. & Wiemels, J. Origins of chromosome translations in childhood leukaemia. Nature Rev. Cancer 3, 639-649 (2003).
83. Schwieger, M. et al. AML1-ETO inhibits maturation of multiple lymphohematopoietic lineages and induces myeloblast transformation in synergy with ICSBP deficiency. J. Exp. Med. 196, 1227-1240 (2002).
84. Yuan, Y. et al. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc. Natl Acad. Sci. USA 98, 10398-10403 (2001).
85. Dann, E. J., Fears, S., Arad-Dann, H., Nucifora, G. & Rowley, J. D. Lineage specificity of CBFA2 fusion transcripts. Leuk. Res. 24, 11-17 (2000).
86. Frank, R. C., Sun, X., Berguido, F. J., Jakubowiak, A. & Nimer, S. D. The t(8;21 ) fusion protein, AML1/ETO, transforms NIH3T3 cells and activates AP-1. Oncogene 18, 1701-1710 (1999).
87. Kurokawa, M. et al. The AML1/Evi-1 fusion protein in the t(3;21) translocation exhibits transforming activity on Rat1 fibroblasts with dependence on the Evi-1 sequence Oncogene 11, 833-840 (1995).
88. Gunji, H. et al. TEL/AML1 shows dominant-negative effects over TEL as well as AML1. Biochem. Biophys. Res. Commun. 322, 623-630 (2004).
89. Klampfer, L., Zhang, J., Zelenetz, A. O., Uchida, H. & Nimer, S. D. The AML1/ETO fusion protein activates transcription of BCL-2. Proc. Natl Acad. Sci. USA 93, 14059-14064 (1996).
90. Zhang, J., Kalkum, M., Yamamura, S., Chait, B. T. & Roeder, R. G. E protein silencing by the leukemogenic AML1-ETO fusion protein. Science 305, 1286-1289 (2004).
91. Muller-Tidow, C. et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol. Cell. Biol. 24, 2890-2904 (2004).
92. Cuenco, G. M. & Ren, R. Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia. Oncogene 20, 8236-8248 (2001).
93. Wiemels, J. L. et al. Prenatal origin of acute lymphoblastic leukaemia in children. Lancet 354, 1499-1503 (1999). Demonstrated that leukaemia-associated TEL-RUNX1 translocations could arise before birth. This finding emphasises the importance of secondary events and the long latency period involved in this disease process.
94. Mori, H. et al. Chromosome translations and covert leukemic clones are generated during normal fetal development. Proc. Natl Acad. Sci. USA 99, 8242-8247 (2002).
95. Raynaud, S. et al. The 12;21 translocation involving TEL and deletion of the other TEL allele: two frequently associated alterations found in childhood acute lymphoblastic leukemia. Blood 87, 2891-2899 (1996).
96. Zuna, J. et al. TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia. Clin. Cancer Res. 10, 5355-5360 (2004).
97. Grisolano, J. L., O'Neal, J., Cain, J. & Tomasson, M. H. An activated receptor tyrosine kinase. TEL/PDGFβR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc. Natl Acad. Sci. USA 100, 9506-9511 (2003).
98. Higuchi, M. et al. Expression of aconditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 1, 63-74 (2002). Described a transgenic model that might recapitulate the changes that occur following the somatic acquisition of the RUNX1-ETO translocation. Transgenic mice expressing RUNX1-ETO show enhanced self-renewal of myeloid progenitors and a predisposition to leukaemia.
99. Bernardin, F. et al. TEL-AML1, expressed from t(12;21) in human acute lymphocytic leukemia, induces acute leukemia in mice. Cancer Res. 62, 3904-3908 (2002). Described the first animal model system to demonstrate the oncogenic potential of the TEL-RUNX1 translocation product in vivo. The study showed further that inactivation of the tumour suppressors p16 (INK4A) and p19 (ARF) could collaborate with TEL-RUNX1 to induce leukaemia.
100. Castilla, L. H. et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nature Genet. 23, 144-146 (1999). This paper described the effect the inv(16) translocation has on myeloid differentiation and leukaemogenesis in vivo using a chimeric knock-in model system.
101. deBruijn, M. F. & Speck, N. A. Core-binding factors in hematopoiesis and immune function. Oncogene 23, 4238-4248 (2004).
102. Levanon, D. et al. Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1. Gene 262, 23-33 (2001).
103. Stewart, M. et al. Proviral insertions induce the expression of bone-specific isoforms of PEBP2αA (CBFA1): evidence for a new myc collaborating oncogene. Proc. Natl Acad. Sci. USA 94, 8646-8651 (1997). Provided the first evidence that Runx2 could act as a target for retroviral activation in murine T-cell leukaemia. Together with reference 115, this was the first definitive evidence that full-length, wild-type RUNX products could act as dominant oncogenes.
104. Stewart, M. et al. til-1: a novel proviral insertion locus for Moloney murine leukaemia virus in lymphomas of CD2-myc transgenic mice. J. Gen. Virol. 77 (Pt 3), 443-446 (1996).
105. Castilla, L. H. et al. Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proc. Natl Acad. Sci. USA 101, 4924-4929 (2004).
106. Li, J. et al. Leukaemia disease genes: large-scale cloning and pathway predictions. Nature Genet. 23, 348-353 (1999).
107. Mikkers, H. et al. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nature Genet. 32, 153-159 (2002).
108. Suzuki, T. et al. New genes involved in cancer identified by retroviral tagging. Nature Genet. 32, 166-174 (2002).
109. Wotton, S. et al. Proviral insertion indicates a dominant oncogenic role for Runx1/AML-1 in T-cell lymphoma. Cancer Res. 62, 7181-7185 (2002).
110. Kim, R. et al. Genome-based identification of cancer genes by proviral tagging in mouse retrovirus-induced T-cell lymphomas. J. Virol. 77, 2056-2062 (2003).
111. Lund, A. H. et al. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nature Genet. 32, 160-165 (2002).
112. Stewart, M., Mackay, N., Cameron, E. R. & Nell, J. C. The common retroviral insertion locus Dsi1 maps 30 kilobases upstream of the P1 promoter of the murine Runx3/Cbfa3/ Aml2 gene. J. Virol. 76, 4364-4369 (2002).
113. Shin, M. S. et al. High-throughput retroviral tagging for identification of genes invoked in initiation and progression of mouse splenic marginal zone lymphomas. Cancer Res. 64, 4419-4427 (2004).
114. Tanaka, T. et al. An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms. EMBO J. 14, 341-350 (1995).
115. Vaillant, F. et al. A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc. Oncogene 18, 7124-7134 (1999).
116. Niini T., Kanerva, J., Vettenranta, K., Saarinen-Pihkala, U. M. & Knuutila, S. AML1 gene amplification: a novel finding in childhood acute lymphoblastic leukemia. Haematologica 85, 362-366 (2000).
117. Harewood, L. et al. Amplification of AML1 on a duplicated chromosome 21 in acute lymphoblastic leukemia: a study of 20 cases. Leukemia 17, 547-553 (2003).
118. Robinson, H. M. et al. Amplification of AML1 in acute lymphoblastic leukemia is associated with a poor outcome. Leukemia 17, 2249-2250 (2003).
119. Roumier, C. et al. New mechanisms of AML1 gene alteration in hematological malignancies. Leukemia 17, 9-16 (2003).
120. Zipursky, A., Poon, A. & Doyle, J. Leukemia in Down syndrome: a review. Pediatr. Hematol. Oncol. 9, 139-149 (1992).
121. Creutzig, U. et al. Myelodysplasia and acute myelogenous leukemia in Down's syndrome. A report of 40 children of the AML-BFM Study Group, Leukemia 10, 1677-1686 (1996).
122. Hasle, H., Clemmensen, I. H., & Mikkelsen, M. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet 355, 165-169 (2000).
123. Penther, D. et al. Amplification of AML1 gene is present in childhood acute lymphoblastic leukemia but not in adult, and is not associated with AML1 gene mutation. Leukemia 16, 1131-1134 (2002).
124. Busson-Le Coniat, M., Nguyen, K. F., Daniel, M. T., Bernard, O. A. & Berger, R. Chromosome 21 abnormalities with AML1 amplification in acute lymphoblastic leukemia Genes Chromosom. Cancer 32, 244-249 (2001).
125. Niini, T. et al. Expression of myeloid-specific genes in childhood acute lymphoblastic leukemia: a cDNA array study. Leukemia 16, 2213-2221 (2002).
126. Mikhail, F. M. et al. AML1 gene over-expression in childhood acute lymphoblastic leukemia. Leukemia 16, 658-668 (2002).
127. Planaguma, J. et al. A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma. Cancer Res. 64, 8846-8853 (2004).
128. Kurokawa, M. et al. Overexpression of the AML1 protooncoprotein in NIH3T3 cells leads to neoplastic transformation depending on the DNA-binding and transactivational potencies. Oncogene 12, 883-892 (1996).
129. Wotton, S. F. et al. RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53. Oncogene 23, 5476-5486 (2004).
130. Linggi, B. et al. The t(8;21)fusion protein, AML1 ETO, specifically represses the transcription of the p14ARF tumor suppressor in acute myeloid leukemia. Nature Med. 8, 743-750 (2002).
131. Telfer, J. C., Hedblom, E. E., Anderson, M. K., Laurent, M. N. & Rothenberg, E. V. Localization of the domains in Runx transcription factors required for the repression of CD4 in thymocytes. J. Immunol. 172, 4359-4370 (2004).
132. Strom, D. K. et al. Expression of the AML-1 oncogene shortens the G(1) phase of the cell cycle. J. Biol. Chem. 275, 3438-3445 (2000).
133. Bernardin-Fried, F. et al. AML1/RUNX1 increases during G1 to S cell cycle progression independent of cytokine-dependent phosphorylation and induces cyclin D3 gene expression. J. Biol. Chem. 279, 15678-15687 (2004).
134. Forus, A. et al. Comparative genomic hybridization analysis of human sarcomas: II. Identification of novel amplicons at 6p and 17p in osteosarcomas. Genes Chromosom. Cancer 14, 15-21 (1995).
135. Lau, C. C. et al. Frequent amplification and rearrangement of chromosomal bands 6p12-p21 and 17p11.2 in osteosarcoma. Genes Chromosom. Cancer 39.11-21 (2004).
136. Vaillant, F., Blyth, K., Andrew, L., Neil, J. C. & Cameron, E. R. Enforced expression of Runx2 perturbs T cell development at a stage coincident with β-selection. J. Immunol. 169, 2866-2874 (2002).
137. Blyth, K. et al. Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging. Oncogene 20, 295-302 (2001).
138. Sun, L., Vitolo, M. & Passaniti, A. Runt-related gene 2 in endothelial cells: inducible expression and specific regulation of cell migration and invasion. Cancer Res. 61, 4994-5001 (2001).
139. Zelzer, E. et al. Tissue specific regulation of VEGF expression during bone development requires Cbfa1/ Runx2. Mech. Dev. 106, 97-106 (2001).
140. Sun, L., Vitolo, M. I., Qiao, M., Anglin, I. E. & Passaniti, A. Regulation of TGFβ1-mediated growth inhibition and apoptosis by RUNX2 isoforms in endothelial cells. Oncogene 23, 4722-4734 (2004).
141. Fujita, T. et al. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. J. Cell Biol. 166, 85-95 (2004).
142. Xiao, G., Jiang, D., Gopalakrishnan, R. & Franceschi, R. T. Fibroblast growth factor 2 induction of the osteocalcin gene requires MAPK activity and phosphorylation of the osteoblast transcription factor, Cbfa1/Runx2. J. Biol. Chem. 277, 36181-36187 (2002).
143. Kim, H. J. et al. The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J. Biol. Chem. 278, 319-326 (2003).
144. Qiao, M., Shapiro, P., Kumar, R. & Passaniti, A. Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ ERK-dependent and Akt-independent signaling pathway. J. Biol. Chem. 279, 42709-42718 (2004).
145. Ducy P., Zhang, R., Geoffroy, V., Ridall, A. L. & Karsenty, G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell 89, 747-754 (1997).
146. Inman, C. K. & Shore, P. The osteoblast transcription factor Runx2 is expressed in mammary epithelial cells and mediates osteopontin expression. J. Biol. Chem. 278, 48684-48689 (2003).
147. Jimenez, M. J. et al. Collagenase 3 is a target of Cbfa1, a transcription factor of the runt gene family involved in bone formation. Mol. Cell. Biol. 19, 4431-4442 (1999).
148. Selvamurugan, N., Kwok, S. & Partridge, N. C. Smad3 interacts with JunB and Cbfa1/Runx2 for transforming growth factor-β1 -stimulated collagenase-3 expression in human breast cancer cells. J. Biol. Chem. 279, 27764-27773 (2004).
149. Barnes, G. L. et al. Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease. Cancer Res. 64, 4506-4513 (2004).
150. Yang, J. et al. Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway. Cancer Res. 61, 5652-5659 (2001).
151. Barnes, G. L. et al. Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoproteln in human metastatic breast cancer cells Cancer Res. 63, 2631-2637 (2003).
152. Brubaker, K. D., Vessella, R. L., Brown, L. G. & Corey, E. Prostate cancer expression of runt-domain transcription factor Runx2, a key regulator of osteoblast differentiation and function. Prostate 56, 13-22 (2003).
153. Yeung, F. et al. Regulation of human osteocalcin promoter in hormone-independent human prostate cancer cells, J. Biol. Chem. 277, 2468-2476 (2002).
154. Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nature Rev. Cancer 3, 453-458 (2003).
155. Li, J. et al. RUNX3 expression in primary and metastatic pancreatic cancer. J. Clin. Pathol. 57, 294-299 (2004).
156. Lacayo, N. J. et al. Gene expression profiles at diagnosis in de novo childhood AML patients identify FLT3 mutations with good clinical outcomes. Blood 104, 2646-2654 (2004).
157. Debernardi, S. et al. Genome-wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation-mediated fusion events. Genes Chromosom. Cancer 37, 149-158 (2003).
158. Spender, L. C., Cornish, G. H., Sullivan, A. & Farrell, P. J. Expression of transcription factor AML-2 (RUNX3, CBF(α)-3) is induced by Epstein-Barr virus EBNA-2 and correlates with the B-cell activation phenotype. J. Virol. 78, 4919-4927 (2002).
159. Spender, L. C., Whiteman, H. J., Karstegl, C. E. & Farrell, P. J. Transcriptional cross-regulation of RUNX1 by RUNX3 in human B cells. Oncogene 24, 1873-1881 (2005).
160. Lutterbach, B. et al. A mechanism of repression by acute myeloid leukemia-1, the target of multiple chromosomal translocations in acute leukemia. J. Biol. Chem. 275, 651-656 (2000).
161. Westendorf, J. J. et al. Runx2′(Cbfal, AML-3) interacts with histone deacetylase 6 and represses the p21CIP/WAF1 promoter. Mol. Cell. Biol. 22, 7982-7992 (2002).
162. Pratap, J. et al. Cell growth regulatory role of Runx2 during proliferative expansion of preosteoblasts. Cancer Res. 63, 5357-5362 (2003).
163. KIP1, is disrupted in osteosarcoma. J. Cell Biol. 167, 925-934 (2004).
164. Hanai, J. et al. Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline Cα promoter J. Biol. Chem. 274, 31577-31582 (1999).
165. Lee, K. S. et al. Runx2 is a common target of transforming growth factor ß1 and bone morphogenetic protein 2, and cooperation between Runx2 and Smad5 induces osteoblast-specific gene expression in the pluripotent mesenchymal precursor cell line C2C12. Mol. Cell. Biol. 20, 8783-8792 (2000).
166. Lee, K. S., Hong, S. H. & Bae, S. C. Both the Smad and p38 MARK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-β and bone morphogenetic protein. Oncogens 21, 7156-7163 (2002).
167. Ji, C. et al. CBFa(AML/PEBP2)-related elements in the TGF-β type I receptor promoter and expression with osteoblast differentiation. J. Cell Biochem. 69, 353-363 (1998).
168. Kurokawa, M. et al. The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-β-mediated growth inhibition of myeloid cells. Blood 92, 4003-1012 (1998).
169. Jakubowiak, A. et al. Inhibition of the transforming growth factor β1 signaling pathway by the AML1/ETO leukemia-associated fusion protein. J. Biol. Chem. 275, 40282-40287 (2000).
170. Westendorf, J. J. & Hiebert, S. W. Mammalian runt-domain proteins and their roles in hematopoiesis, osteogenesis, and leukemia. J. Cell Biochem. 75(Suppl. 32), 51-58 (1999).
171. North, T. et al. Cbfa2 is required for the formation of intraaortic hematopoietic clusters. Development 126, 2563-2575 (1999).
172. Theriault, F. M., Roy, P. & Stifani, S. AML1/Runx1 is important for the development of hindbrain cholinergic branchiovisceral motor neurons and selected cranial sensory neurons. Proc. Natl Acad. Sci USA 101, 10343-10348 (2004).
173. Cai, Z. et al. Haploinsuffidency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo. Immunity. 13, 423-431 (2000).
174. Sun, W. & Downing, J. R. Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors. Blood 104, 3565-3572 (2004).
175. Gao, Y. H. et al. Potential role of cbfa1, an essential transcriptional factor for osteoblast differentiation, in osteoclastogenesis: regulation of mRNA
176. Kim, I. S. Otto, F., Zabel, B. & Mundlos, S. Regulation of chondrocyte differentiation by Cbfa1. Mech. Dev. 80, 159-170 (1999).
177. Inada, M. et al. Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev. Dyn. 214, 279-290 (1999).
178. D'Souza, R. N. et al. Cbfa1 is required for epithelialmesenchymal interactions regulating tooth development in mice. Development 126, 2911-2920 (1999).
179. Fainaru, O. et al. Runx3 regulates mouse TGF-β-mediated dendritic cell function and its absence results in airway inflammation. EMBO J. 23, 969-979 (2004).
180. Sasaki, K. et al. Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor β. Proc. Natl Acad Sci. USA 93, 12359-12363 (1996).
181. Wang, Q. et al. The CBFβ subunit is essential for CBFα2 (AML1) function in vivo. Cell 87, 697-708 (1936).
182. Kundu, M. et al. Cbfβ interacts with Runx2 and has acritical role in bone development. Nature Genet 32, 639-644 (2002).
183. Miller, J. et al. The core-binding factor β subunit is required for bone formation and hematopoietic maturation. Nature Genet. 32, 645-649 (2002).
184. Yoshida, C. A. et al. Core-binding factor β interacts with Runx2 and is required for skeletal development. Nature Genet. 32, 633-638 (2002).