Skip to main content
SpringerLink
Log in
Book cover

RUNX Proteins in Development and Cancer pp 247–264Cite as

The RUNX Genes as Conditional Oncogenes: Insights from Retroviral Targeting and Mouse Models

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 962))

Abstract

The observation that the Runx genes act as targets for transcriptional activation by retroviral insertion identified a new family of dominant oncogenes. However, it is now clear that Runx genes are ‘conditional’ oncogenes whose over-expression is growth inhibitory unless accompanied by another event such as concomitant over-expression of MYC or loss of p53 function. Remarkably, while the oncogenic activities of either MYC or RUNX over-expression are suppressed while p53 is intact, the combination of both neutralises p53 tumour suppression in vivo by as yet unknown mechanisms. Moreover, there is emerging evidence that endogenous, basal RUNX activity is important to maintain the viability and proliferation of MYC-driven lymphoma cells. There is also growing evidence that the human RUNX genes play a similar conditional oncogenic role and are selected for over-expression in end-stage cancers of multiple types. Paradoxically, reduced RUNX activity can also predispose to cell immortalisation and transformation, particularly by mutant Ras. These apparently conflicting observations may be reconciled in a stage-specific model of RUNX involvement in cancer. A question that has yet to be fully addressed is the extent to which the three Runx genes are functionally redundant in cancer promotion and suppression.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Bauer, O., Sharir, A., Kimura, A., Hantisteanu, S., Takeda, S., & Groner, Y. (2015). Loss of osteoblast Runx3 produces severe congenital osteopenia. Molecular and Cellular Biology, 35, 1097–1109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ben-Ami, O., Friedman, D., Leshkowitz, D., Goldenberg, D., Orlovsky, K., Pencovich, N., et al. (2013). Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1. Cell Reports, 4, 1131–1143.

    Article  CAS  PubMed  Google Scholar 

  • Bledsoe, K. L., McGee-Lawrence, M. E., Camilleri, E. T., Wang, X., Riester, S. M., van Wijnen, A. J., et al. (2014). RUNX3 facilitates growth of Ewing sarcoma cells. Journal of Cellular Physiology, 229, 2049–2056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blyth, K., Terry, A., O’Hara, M., Baxter, E. W., Campbell, M., Stewart, M., et al. (1995). Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: Contrasting effects of homozygous and heterozygous p53 loss. Oncogene, 10, 1717–1723.

    CAS  PubMed  Google Scholar 

  • Blyth, K., Terry, A., Mackay, N., Vaillant, F., Bell, M., Cameron, E. R., et al. (2001). Runx2: A novel oncogenic effector revealed by in vivo complementation and retroviral tagging. Oncogene, 20, 295–302.

    Article  CAS  PubMed  Google Scholar 

  • Blyth, K., Vaillant, F., Hanlon, L., Mackay, N., Bell, M., Jenkins, A., et al. (2006). Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo. Cancer Research, 66, 2195–2201.

    Article  CAS  PubMed  Google Scholar 

  • Blyth, K., Slater, N., Hanlon, L., Bell, M., Mackay, N., Stewart, M., et al. (2009). Runx1 promotes B-cell survival and lymphoma development. Blood Cells, Molecules & Diseases, 43, 12–19.

    Article  CAS  Google Scholar 

  • Borland, G., Kilbey, A., Hay, J., Gilroy, K., Terry, A., Mackay, N., et al. (2016). Addiction to Runx1 is partially attenuated by loss of p53 in the Emu-Myc lymphoma model. Oncotarget, 7, 22973–22987.

    PubMed  PubMed Central  Google Scholar 

  • Brady, G., Whiteman, H. J., Spender, L. C., & Farrell, P. J. (2009). Downregulation of RUNX1 by RUNX3 requires the RUNX3 VWRPY sequence and is essential for Epstein-Barr virus-driven B-cell proliferation. Journal of Virology, 83, 6909–6916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brenner, O., Levanon, D., Negreanu, V., Golubkov, O., Fainaru, O., Woolf, E., & Groner, Y. (2004). Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia. Proceedings of the National Academy of Sciences of the United States of America, 101, 16016–16021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Browne, G., Dragon, J. A., Hong, D., Messier, T. L., Gordon, J. A., Farina, N. H., et al. (2016). MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells. Tumour Biology, 37, 8825–8839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai, X., Gao, L., Teng, L., Ge, J., Oo, Z. M., Kumar, A. R., et al. (2015). Runx1 deficiency decreases ribosome biogenesis and confers stress resistance to hematopoietic stem and progenitor cells. Cell Stem Cell, 17, 165–177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cameron, E. R., Blyth, K., Hanlon, L., Kilbey, A., Mackay, N., Stewart, M., et al. (2003). The Runx genes as dominant oncogenes. Blood Cells, Molecules & Diseases, 30, 194–200.

    Article  CAS  Google Scholar 

  • Castilla, L. H., Perrat, P., Martinez, N. J., Landrette, S. F., Keys, R., Oikemus, S., et al. (2004). Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America, 101, 4924–4929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cattoglio, C., Pellin, D., Rizzi, E., Maruggi, G., Corti, G., Miselli, F., et al. (2010). High-definition mapping of retroviral integration sites identifies active regulatory elements in human multipotent hematopoietic progenitors. Blood, 116, 5507–5517.

    Article  CAS  PubMed  Google Scholar 

  • Chin, D. W., Watanabe-Okochi, N., Wang, C. Q., Tergaonkar, V., & Osato, M. (2015). Mouse models for core binding factor leukemia. Leukemia, 29, 1970–1980.

    Article  CAS  PubMed  Google Scholar 

  • Cohen-Solal, K. A., Boregowda, R. K., & Lasfar, A. (2015). RUNX2 and the PI3K/AKT axis reciprocal activation as a driving force for tumor progression. Molecular Cancer, 14, 137.

    Article  PubMed  PubMed Central  Google Scholar 

  • de Bruijn, M. F., & Speck, N. A. (2004). Core-binding factors in hematopoiesis and immune function. Oncogene, 23, 4238–4248.

    Article  PubMed  Google Scholar 

  • De Rijck, J., de Kogel, C., Demeulemeester, J., Vets, S., El Ashkar, S., Malani, N., et al. (2013). The BET family of proteins targets moloney murine leukemia virus integration near transcription start sites. Cell Reports, 5, 886–894.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Della Gatta, G., Palomero, T., Perez-Garcia, A., Ambesi-Impiombato, A., Bansal, M., Carpenter, Z. W., et al. (2012). Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nature Medicine, 18, 436–440.

    Article  CAS  PubMed  Google Scholar 

  • Di Micco, R., Fumagalli, M., Cicalese, A., Piccinin, S., Gasparini, P., Luise, C., et al. (2006). Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 444, 638–642.

    Article  CAS  PubMed  Google Scholar 

  • Etzold, A., Galetzka, D., Weis, E., Bartsch, O., Haaf, T., Spix, C., et al. (2016). CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue. Epigenetics, 11, 1–12.

    Article  Google Scholar 

  • Ferrari, N., Riggio, A. I., Mason, S., McDonald, L., King, A., Higgins, T., et al. (2015). Runx2 contributes to the regenerative potential of the mammary epithelium. Scientific Reports, 5, 15658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii, M., Hayashi, K., Niki, M., Chiba, N., Meguro, K., Endo, K., et al. (1998). Overexpression of AML1 renders a T hybridoma resistant to T cell receptor-mediated apoptosis. Oncogene, 17, 1813–1820.

    Article  CAS  PubMed  Google Scholar 

  • Fukushima-Nakase, Y., Naoe, Y., Taniuchi, I., Hosoi, H., Sugimoto, T., & Okuda, T. (2005). Shared and distinct roles mediated through C-terminal subdomains of acute myeloid leukemia/Runt-related transcription factor molecules in murine development. Blood, 105, 4298–4307.

    Article  CAS  PubMed  Google Scholar 

  • Gamberi, G., Benassi, M. S., Bohling, T., Ragazzini, P., Molendini, L., Sollazzo, M. R., et al. (1998). C-myc and c-fos in human osteosarcoma: Prognostic value of mRNA and protein expression. Oncology, 55, 556–563.

    Article  CAS  PubMed  Google Scholar 

  • Goyama, S., Yamaguchi, Y., Imai, Y., Kawazu, M., Nakagawa, M., Asai, T., et al. (2004). The transcriptionally active form of AML1 is required for hematopoietic rescue of the AML1-deficient embryonic para-aortic splanchnopleural (P-Sp) region. Blood, 104, 3558–3564.

    Article  CAS  PubMed  Google Scholar 

  • Grossmann, V., Kern, W., Harbich, S., Alpermann, T., Jeromin, S., Schnittger, S., et al. (2011). Prognostic relevance of RUNX1 mutations in T-cell acute lymphoblastic leukemia. Haematologica, 96, 1874–1877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta, S. S., Maetzig, T., Maertens, G. N., Sharif, A., Rothe, M., Weidner-Glunde, M., et al. (2013). Bromo- and extraterminal domain chromatin regulators serve as cofactors for murine leukemia virus integration. Journal of Virology, 87, 12721–12736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hacein-Bey-Abina, S., Garrigue, A., Wang, G. P., Soulier, J., Lim, A., Morillon, E., et al. (2008). Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. The Journal of Clinical Investigation, 118, 3132–3142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harrington, E. A., Bennett, M. R., Fanidi, A., & Evan, G. I. (1994). c-Myc-induced apoptosis in fibroblasts is inhibited by specific cytokines. The EMBO Journal, 13, 3286–3295.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harrison, C. J., Moorman, A. V., Schwab, C., Carroll, A. J., Raetz, E. A., Devidas, M., et al. (2014). An international study of intrachromosomal amplification of chromosome 21 (iAMP21): Cytogenetic characterization and outcome. Leukemia, 28, 1015–1021.

    Article  CAS  PubMed  Google Scholar 

  • Hermeking, H., & Eick, D. (1994). Mediation of c-Myc-induced apoptosis by p53. Science, 265, 2091–2093.

    Article  CAS  PubMed  Google Scholar 

  • Howe, S. J., Mansour, M. R., Schwarzwaelder, K., Bartholomae, C., Hubank, M., Kempski, H., et al. (2008). Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. The Journal of Clinical Investigation, 118, 3143–3150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu, B., Marin, M. C., el-Naggar, A. K., Stephens, L. C., Brisbay, S., & McDonnell, T. J. (1995). Evidence that c-myc mediated apoptosis does not require wild-type p53 during lymphomagenesis. Oncogene, 11, 175–179.

    CAS  PubMed  Google Scholar 

  • Huser, C. A., Gilroy, K. L., de Ridder, J., Kilbey, A., Borland, G., Mackay, N., et al. (2014). Insertional mutagenesis and deep profiling reveals gene hierarchies and a Myc/p53-dependent bottleneck in lymphomagenesis. PLoS Genetics, 10, e1004167.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hwang, H. C., Martins, C. P., Bronkhorst, Y., Randel, E., Berns, A., Fero, M., & Clurman, B. E. (2002). Identification of oncogenes collaborating with p27Kip1 loss by insertional mutagenesis and high-throughput insertion site analysis. Proceedings of the National Academy of Sciences of the United States of America, 99, 11293–11298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobs, J. J., Scheijen, B., Voncken, J. W., Kieboom, K., Berns, A., & van Lohuizen, M. (1999). Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes & Development, 13, 2678–2690.

    Article  CAS  Google Scholar 

  • Khandanpour, C., & Moroy, T. (2013). Growth factor independence 1 (Gfi1) as a regulator of p53 activity and a new therapeutical target for ALL. Oncotarget, 4, 374–375.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kilbey, A., Blyth, K., Wotton, S., Terry, A., Jenkins, A., Bell, M., et al. (2007). Runx2 disruption promotes immortalization and confers resistance to oncogene-induced senescence in primary murine fibroblasts. Cancer Research, 67, 11263–11271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kilbey, A., Terry, A., Cameron, E. R., & Neil, J. C. (2008). Oncogene-induced senescence: An essential role for Runx. Cell Cycle, 7, 2333–2340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kilbey, A., Terry, A., Jenkins, A., Borland, G., Zhang, Q., Wakelam, M. J., et al. (2010). Runx regulation of sphingolipid metabolism and survival signaling. Cancer Research, 70, 5860–5869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kundu, M., Compton, S., Garrett-Beal, L., Stacy, T., Starost, M. F., Eckhaus, M., et al. (2005). Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma. Blood, 106, 3621–3624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuo, Y. H., Zaidi, S. K., Gornostaeva, S., Komori, T., Stein, G. S., & Castilla, L. H. (2009). Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice. Blood, 113, 3323–3332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • LaFave, M. C., Varshney, G. K., Gildea, D. E., Wolfsberg, T. G., Baxevanis, A. D., & Burgess, S. M. (2014). MLV integration site selection is driven by strong enhancers and active promoters. Nucleic Acids Research, 42, 4257–4269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee, Y. S., Lee, J. W., Jang, J. W., Chi, X. Z., Kim, J. H., Li, Y. H., et al. (2013). Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma. Cancer Cell, 24, 603–616.

    Article  PubMed  Google Scholar 

  • Levanon, D., Glusman, G., Bangsow, T., Ben-Asher, E., Male, D. A., Avidan, N., et al. (2001). Architecture and anatomy of the genomic locus encoding the human leukemia-associated transcription factor RUNX1/AML1. Gene, 262, 23–33.

    Article  CAS  PubMed  Google Scholar 

  • Liakhovitskaia, A., Lana-Elola, E., Stamateris, E., Rice, D. P., van’t Hof, R. J., & Medvinsky, A. (2010). The essential requirement for Runx1 in the development of the sternum. Developmental Biology, 340, 539–546.

    Article  CAS  PubMed  Google Scholar 

  • Lilljebjorn, H., Soneson, C., Andersson, A., Heldrup, J., Behrendtz, M., Kawamata, N., et al. (2010). The correlation pattern of acquired copy number changes in 164 ETV6/RUNX1-positive childhood acute lymphoblastic leukemias. Human Molecular Genetics, 19, 3150–3158.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lilljebjorn, H., Rissler, M., Lassen, C., Heldrup, J., Behrendtz, M., Mitelman, F., et al. (2012). Whole-exome sequencing of pediatric acute lymphoblastic leukemia. Leukemia, 26, 1602–1607.

    Article  CAS  PubMed  Google Scholar 

  • Linggi, B., Muller-Tidow, C., van de Locht, L., Hu, M., Nip, J., Serve, H., et al. (2002). The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia. Nature Medicine, 8, 743–750.

    Article  CAS  PubMed  Google Scholar 

  • Lu, X. Y., Lu, Y., Zhao, Y. J., Jaeweon, K., Kang, J., Xiao-Nan, L., et al. (2008). Cell cycle regulator gene CDC5L, a potential target for 6p12-p21 amplicon in osteosarcoma. Molecular Cancer Research, 6, 937–946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malynn, B. A., de Alboran, I. M., O’Hagan, R. C., Bronson, R., Davidson, L., DePinho, R. A., & Alt, F. W. (2000). N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation. Genes & Development, 14, 1390–1399.

    CAS  Google Scholar 

  • Mead, A. J., Kharazi, S., Atkinson, D., Macaulay, I., Pecquet, C., Loughran, S., et al. (2013). FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors. Cell Reports, 3, 1766–1776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miething, C., Grundler, R., Mugler, C., Brero, S., Hoepfl, J., Geigl, J., et al. (2007). Retroviral insertional mutagenesis identifies RUNX genes involved in chronic myeloid leukemia disease persistence under imatinib treatment. Proceedings of the National Academy of Sciences of the United States of America, 104, 4594–4599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mikkers, H., Allen, J., Knipscheer, P., Romeijn, L., Hart, A., Vink, E., & Berns, A. (2002). High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nature Genetics, 32, 153–159.

    Article  CAS  PubMed  Google Scholar 

  • Motoda, L., Osato, M., Yamashita, N., Jacob, B., Chen, L. Q., Yanagida, M., et al. (2007). Runx1 protects hematopoietic stem/progenitor cells from oncogenic insult. Stem Cells, 25, 2976–2986.

    Article  CAS  PubMed  Google Scholar 

  • Niini, T., Vettenranta, K., Hollmen, J., Larramendy, M. L., Aalto, Y., Wikman, H., et al. (2002). Expression of myeloid-specific genes in childhood acute lymphoblastic leukemia – A cDNA array study. Leukemia, 16, 2213–2221.

    Article  CAS  PubMed  Google Scholar 

  • Owen, C. J., Toze, C. L., Koochin, A., Forrest, D. L., Smith, C. A., Stevens, J. M., et al. (2008). Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood, 112, 4639–4645.

    Article  CAS  PubMed  Google Scholar 

  • Parrinello, S., Samper, E., Krtolica, A., Goldstein, J., Melov, S., & Campisi, J. (2003). Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nature Cell Biology, 5, 741–747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Putz, G., Rosner, A., Nuesslein, I., Schmitz, N., & Buchholz, F. (2006). AML1 deletion in adult mice causes splenomegaly and lymphomas. Oncogene, 25, 929–939.

    Article  CAS  PubMed  Google Scholar 

  • Rudolph, B., Hueber, A. O., & Evan, G. I. (2000). Reversible activation of c-Myc in thymocytes enhances positive selection and induces proliferation and apoptosis in vitro. Oncogene, 19, 1891–1900.

    Article  CAS  PubMed  Google Scholar 

  • Schnerch, D., Lausch, E., Becker, H., Felthaus, J., Pfeifer, D., Mundlos, S., et al. (2014). Up-regulation of RUNX2 in acute myeloid leukemia in a patient with an inherent RUNX2 haploinsufficiency and cleidocranial dysplasia. Leukemia & Lymphoma, 55, 1930–1932.

    Article  CAS  Google Scholar 

  • Schwarzwaelder, K., Howe, S. J., Schmidt, M., Brugman, M. H., Deichmann, A., Glimm, H., et al. (2007). Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. The Journal of Clinical Investigation, 117, 2241–2249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scobie, L., Hector, R. D., Grant, L., Bell, M., Nielsen, A. A., Meikle, S., et al. (2009). A novel model of SCID-X1 reconstitution reveals predisposition to retrovirus-induced lymphoma but no evidence of gammaC gene oncogenicity. Molecular Therapy, 17, 1031–1038.

    Article  CAS  PubMed Central  Google Scholar 

  • Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell, 88, 593–602.

    Article  CAS  PubMed  Google Scholar 

  • Sharma, A., Larue, R. C., Plumb, M. R., Malani, N., Male, F., Slaughter, A., et al. (2013). BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proceedings of the National Academy of Sciences of the United States of America, 110, 12036–12041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimizu, K., Yamagata, K., Kurokawa, M., Mizutani, S., Tsunematsu, Y., & Kitabayashi, I. (2013). Roles of AML1/RUNX1 in T-cell malignancy induced by loss of p53. Cancer Science, 104, 1033–1038.

    Article  CAS  PubMed  Google Scholar 

  • Shin, M. H., He, Y., Marrogi, E., Piperdi, S., Ren, L., Khanna, C., et al. (2016). A RUNX2-mediated epigenetic regulation of the survival of p53 defective cancer cells. PLoS Genetics, 12, e1005884.

    Article  PubMed  PubMed Central  Google Scholar 

  • Spender, L. C., Whiteman, H. J., Karstegl, C. E., & Farrell, P. J. (2005). Transcriptional cross-regulation of RUNX1 by RUNX3 in human B cells. Oncogene, 24, 1873–1881.

    Article  CAS  PubMed  Google Scholar 

  • Stewart, M., Cameron, E., Campbell, M., McFarlane, R., Toth, S., Lang, K., et al. (1993). Conditional expression and oncogenicity of c-myc linked to a CD2 gene dominant control region. International Journal of Cancer, 53, 1023–1030.

    Article  CAS  PubMed  Google Scholar 

  • Stewart, M., Terry, A., Hu, M., O’Hara, M., Blyth, K., Baxter, E., et al. (1997). Proviral insertions induce the expression of bone-specific isoforms of PEBP2alphaA (CBFA1): Evidence for a new myc collaborating oncogene. Proceedings of the National Academy of Sciences of the United States of America, 94, 8646–8651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart, M., MacKay, N., Cameron, E. R., & Neil, J. C. (2002). The common retroviral insertion locus Dsi1 maps 30 kilobases upstream of the P1 promoter of the murine Runx3/Cbfa3/Aml2 gene. Journal of Virology, 76, 4364–4369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart, M., Mackay, N., Hanlon, L., Blyth, K., Scobie, L., Cameron, E., & Neil, J. C. (2007). Insertional mutagenesis reveals progression genes and checkpoints in MYC/Runx2 lymphomas. Cancer Research, 67, 5126–5133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strefford, J. C., van Delft, F. W., Robinson, H. M., Worley, H., Yiannikouris, O., Selzer, R., et al. (2006). Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21. Proceedings of the National Academy of Sciences of the United States of America, 103, 8167–8172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki, T., Shen, H., Akagi, K., Morse, H. C., Malley, J. D., Naiman, D. Q., et al. (2002). New genes involved in cancer identified by retroviral tagging. Nature Genetics, 32, 166–174.

    Article  CAS  PubMed  Google Scholar 

  • Taniuchi, I., Osato, M., Egawa, T., Sunshine, M. J., Bae, S. C., Komori, T., et al. (2002). Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell, 111, 621–633.

    Article  CAS  PubMed  Google Scholar 

  • Uren, A. G., Kool, J., Berns, A., & van Lohuizen, M. (2005). Retroviral insertional mutagenesis: Past, present and future. Oncogene, 24, 7656–7672.

    Article  CAS  PubMed  Google Scholar 

  • Uren, A. G., Kool, J., Matentzoglu, K., de Ridder, J., Mattison, J., van Uitert, M., et al. (2008). Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks. Cell, 133, 727–741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vaillant, F., Blyth, K., Terry, A., Bell, M., Cameron, E. R., Neil, J., & Stewart, M. (1999). A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc. Oncogene, 18, 7124–7134.

    Article  CAS  PubMed  Google Scholar 

  • Vaillant, F., Blyth, K., Andrew, L., Neil, J. C., & Cameron, E. R. (2002). Enforced expression of Runx2 perturbs T cell development at a stage coincident with beta-selection. Journal of Immunology, 169, 2866–2874.

    Article  CAS  Google Scholar 

  • van der Weyden, L., Papaspyropoulos, A., Poulogiannis, G., Rust, A. G., Rashid, M., Adams, D. J., et al. (2012). Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis. Cancer Research, 72, 3817–3827.

    Article  PubMed  PubMed Central  Google Scholar 

  • Vijaya, S., Steffen, D. L., Kozak, C., & Robinson, H. L. (1987). Dsi-1, a region with frequent proviral insertions in Moloney murine leukemia virus-induced rat thymomas. Journal of Virology, 61, 1164–1170.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, C. Q., Krishnan, V., Tay, L. S., Chin, D. W., Koh, C. P., Chooi, J. Y., et al. (2014). Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects. Cell Reports, 8, 767–782.

    Article  CAS  PubMed  Google Scholar 

  • Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., et al. (2013). Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell, 153, 307–319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams, A., Harker, N., Ktistaki, E., Veiga-Fernandes, H., Roderick, K., Tolaini, M., et al. (2008). Position effect variegation and imprinting of transgenes in lymphocytes. Nucleic Acids Research, 36, 2320–2329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wolyniec, K., Wotton, S., Kilbey, A., Jenkins, A., Terry, A., Peters, G., et al. (2009). RUNX1 and its fusion oncoprotein derivative, RUNX1-ETO, induce senescence-like growth arrest independently of replicative stress. Oncogene, 28, 2502–2512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong, W. F., Kohu, K., Nakamura, A., Ebina, M., Kikuchi, T., Tazawa, R., et al. (2012). Runx1 deficiency in CD4+ T cells causes fatal autoimmune inflammatory lung disease due to spontaneous hyperactivation of cells. Journal of Immunology, 188, 5408–5420.

    Article  CAS  Google Scholar 

  • Wotton, S., Stewart, M., Blyth, K., Vaillant, F., Kilbey, A., Neil, J. C., & Cameron, E. R. (2002). Proviral insertion indicates a dominant oncogenic role for Runx1/AML-1 in T-cell lymphoma. Cancer Research, 62, 7181–7185.

    CAS  PubMed  Google Scholar 

  • Wotton, S. F., Blyth, K., Kilbey, A., Jenkins, A., Terry, A., Bernardin-Fried, F., et al. (2004). RUNX1 transformation of primary embryonic fibroblasts is revealed in the absence of p53. Oncogene, 23, 5476–5486.

    Article  CAS  PubMed  Google Scholar 

  • Wotton, S., Terry, A., Kilbey, A., Jenkins, A., Herzyk, P., Cameron, E., & Neil, J. C. (2008). Gene array analysis reveals a common Runx transcriptional programme controlling cell adhesion and survival. Oncogene, 27, 5856–5866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaidi, S. K., Pande, S., Pratap, J., Gaur, T., Grigoriu, S., Ali, S. A., et al. (2007). Runx2 deficiency and defective subnuclear targeting bypass senescence to promote immortalization and tumorigenic potential. Proceedings of the National Academy of Sciences of the United States of America, 104, 19861–19866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaliova, M., Madzo, J., Cario, G., & Trka, J. (2011). Revealing the role of TEL/AML1 for leukemic cell survival by RNAi-mediated silencing. Leukemia, 25, 313–320.

    Article  CAS  PubMed  Google Scholar 

  • Zindy, F., Eischen, C. M., Randle, D. H., Kamijo, T., Cleveland, J. L., Sherr, C. J., & Roussel, M. F. (1998). Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes & Development, 12, 2424–2433.

    Article  CAS  Google Scholar 

  • Zinkernagel, R. M., Callahan, G. N., Althage, A., Cooper, S., Klein, P. A., & Klein, J. (1978). On the thymus in the differentiation of “H-2 self-recognition” by T cells: Evidence for dual recognition? The Journal of Experimental Medicine, 147, 882–896.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Our work was supported by a joint programme grant from Bloodwise (grant number 13046) and Cancer Research UK (grant number A11951).

Author information

Authors and Affiliations

  1. Molecular Oncology Laboratory, Centre for Virus Research, University of Glasgow, Bearsden, Glasgow, G61 1QH, UK

    James C. Neil, Kathryn Gilroy, Gillian Borland, Jodie Hay, Anne Terry & Anna Kilbey

Authors
  1. James C. Neil
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathryn Gilroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gillian Borland
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jodie Hay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Terry
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anna Kilbey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James C. Neil .

Editor information

Editors and Affiliations

  1. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Yoram Groner

  2. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Yoshiaki Ito

  3. Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, Maryland, USA

    Paul Liu

  4. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom

    James C. Neil

  5. Department of Cell and Development Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Nancy A. Speck

  6. Mayo Clinic, Rochester, Minnesota, USA

    Andre van Wijnen

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Nature Singapore Pte Ltd.

About this chapter

Cite this chapter

Neil, J.C., Gilroy, K., Borland, G., Hay, J., Terry, A., Kilbey, A. (2017). The RUNX Genes as Conditional Oncogenes: Insights from Retroviral Targeting and Mouse Models. In: Groner, Y., Ito, Y., Liu, P., Neil, J., Speck, N., van Wijnen, A. (eds) RUNX Proteins in Development and Cancer. Advances in Experimental Medicine and Biology, vol 962. Springer, Singapore. https://doi.org/10.1007/978-981-10-3233-2_16

Download citation

Publish with us

Policies and ethics

Search

Navigation