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Posttranslational modifications of RUNX1 as potential anticancer targets

Oncogene volume 34, pages 3483–3492 (2015)Cite this article

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Abstract

The transcription factor RUNX1 is a master regulator of hematopoiesis. Disruption of RUNX1 activity has been implicated in the development of hematopoietic neoplasms. Recent studies also highlight the importance of RUNX1 in solid tumors both as a tumor promoter and a suppressor. Given its central role in cancer development, RUNX1 is an excellent candidate for targeted therapy. A potential strategy to target RUNX1 is through modulation of its posttranslational modifications (PTMs). Numerous studies have shown that RUNX1 activity is regulated by PTMs, including phosphorylation, acetylation, methylation and ubiquitination. These PTMs regulate RUNX1 activity either positively or negatively by altering RUNX1-mediated transcription, promoting protein degradation and affecting protein interactions. In this review, we first summarize the available data on the context- and dosage-dependent roles of RUNX1 in various types of neoplasms. We then provide a comprehensive overview of RUNX1 PTMs from biochemical and biologic perspectives. Finally, we discuss how aberrant PTMs of RUNX1 might contribute to tumorigenesis and also strategies to develop anticancer therapies targeting RUNX1 PTMs.

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References

  1. Link KA, Chou FS, Mulloy JC . Core binding factor at the crossroads: determining the fate of the HSC. J Cell Physiol 2010; 222: 50–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Kurokawa M . AML1/Runx1 as a versatile regulator of hematopoiesis: regulation of its function and a role in adult hematopoiesis. Int J Hematol 2006; 84: 136–142.

    CAS  PubMed  Google Scholar 

  3. Wang CQ, Krishnan V, Tay LS, Chin DW, Koh CP, Chooi JY et al. Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects. Cell Rep 2014; 8: 767–782.

    CAS  PubMed  Google Scholar 

  4. Bresciani E, Carrington B, Wincovitch S, Jones M, Gore AV, Weinstein BM et al. CBFbeta and RUNX1 are required at 2 different steps during the development of hematopoietic stem cells in zebrafish. Blood 2014; 124: 70–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Levanon D, Groner Y . Structure and regulated expression of mammalian RUNX genes. Oncogene 2004; 23: 4211–4219.

    CAS  PubMed  Google Scholar 

  6. Wang L, Huang G, Zhao X, Hatlen MA, Vu L, Liu F et al. Post-translational modifications of Runx1 regulate its activity in the cell. Blood Cells Mol Dis 2009; 43: 30–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Bae SC, Lee YH . Phosphorylation, acetylation and ubiquitination: the molecular basis of RUNX regulation. Gene 2006; 366: 58–66.

    CAS  PubMed  Google Scholar 

  8. Scheitz CJ, Tumbar T . New insights into the role of Runx1 in epithelial stem cell biology and pathology. J Cell Biochem 2013; 114: 985–993.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Gorczynski MJ, Grembecka J, Zhou Y, Kong Y, Roudaia L, Douvas MG et al. Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta. Chem Biol 2007; 14: 1186–1197.

    CAS  PubMed  Google Scholar 

  10. Cunningham L, Finckbeiner S, Hyde RK, Southall N, Marugan J, Yedavalli VR et al. Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFbeta interaction. Proc Natl Acad Sci USA 2012; 109: 14592–14597.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Blyth K, Cameron ER, Neil JC . The RUNX genes: gain or loss of function in cancer. Nat Rev Cancer 2005; 5: 376–387.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Goyama S, Schibler J, Cunningham L, Zhang Y, Rao Y, Nishimoto N et al. Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. J Clin Invest 2013; 123: 3876–3888.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wilkinson AC, Ballabio E, Geng H, North P, Tapia M, Kerry J et al. RUNX1 is a key target in t(4;11) leukemias that contributes to gene activation through an AF4-MLL complex interaction. Cell Rep 2013; 3: 116–127.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Goyama S, Mulloy JC . Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects. Int J Hematol 2011; 94: 126–133.

    CAS  PubMed  Google Scholar 

  16. Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H et al. Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia. EMBO J 1994; 13: 504–510.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Osato M . Point mutations in the RUNX1/AML1 gene: another actor in RUNX leukemia. Oncogene 2004; 23: 4284–4296.

    CAS  PubMed  Google Scholar 

  18. Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 1999; 23: 166–175.

    CAS  PubMed  Google Scholar 

  19. Owen CJ, Toze CL, Koochin A, Forrest DL, Smith CA, Stevens JM et al. Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy. Blood 2008; 112: 4639–4645.

    Article  CAS  PubMed  Google Scholar 

  20. Greif PA, Konstandin NP, Metzeler KH, Herold T, Pasalic Z, Ksienzyk B et al. RUNX1 mutations in cytogenetically normal acute myeloid leukemia are associated with a poor prognosis and up-regulation of lymphoid genes. Haematologica 2012; 97: 1909–1915.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Mendler JH, Maharry K, Radmacher MD, Mrozek K, Becker H, Metzeler KH et al. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and microRNA expression signatures. J Clin Oncol 2012; 30: 3109–3118.

    PubMed  PubMed Central  Google Scholar 

  22. Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood 2009; 114: 5352–5361.

    CAS  PubMed  Google Scholar 

  23. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2013; 28: 241–247.

    PubMed  PubMed Central  Google Scholar 

  24. Rocquain J, Carbuccia N, Trouplin V, Raynaud S, Murati A, Nezri M et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer 2010; 10: 401.

    PubMed  PubMed Central  Google Scholar 

  25. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496–2506.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014; 28: 241–247.

    CAS  PubMed  Google Scholar 

  27. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013; 31: 2428–2436.

    CAS  PubMed  Google Scholar 

  28. Schwaab J, Schnittger S, Sotlar K, Walz C, Fabarius A, Pfirrmann M et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013; 122: 2460–2466.

    Article  CAS  PubMed  Google Scholar 

  29. Harada H, Harada Y, Niimi H, Kyo T, Kimura A, Inaba T . High incidence of somatic mutations in the AML1/RUNX1 gene in myelodysplastic syndrome and low blast percentage myeloid leukemia with myelodysplasia. Blood 2004; 103: 2316–2324.

    CAS  PubMed  Google Scholar 

  30. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K et al. Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood 2000; 96: 3154–3160.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Huang G, Zhao X, Wang L, Elf S, Xu H, Zhao X et al. The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. Blood 2011; 118: 6544–6552.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhao X, Chen A, Yan X, Zhang Y, He F, Hayashi Y et al. Down-regulation of RUNX1/CBFbeta by MLL fusion proteins enhances HSC self-renewal. Blood 2014; 123: 1729–1738.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Motoda L, Osato M, Yamashita N, Jacob B, Chen LQ, Yanagida M et al. Runx1 protects hematopoietic stem/progenitor cells from oncogenic insult. Stem Cells 2007; 25: 2976–2986.

    CAS  PubMed  Google Scholar 

  35. Jacob B, Osato M, Yamashita N, Wang CQ, Taniuchi I, Littman DR et al. Stem cell exhaustion due to Runx1 deficiency is prevented by Evi5 activation in leukemogenesis. Blood 2010; 115: 1610–1620.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nishimoto N, Arai S, Ichikawa M, Nakagawa M, Goyama S, Kumano K et al. Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through down-regulation of p19ARF. Blood 2011; 118: 2541–2550.

    CAS  PubMed  Google Scholar 

  37. Kamikubo Y, Zhao L, Wunderlich M, Corpora T, Hyde RK, Paul TA et al. Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1. Cancer Cell 2010; 17: 455–468.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med 2006; 12: 945–949.

    CAS  PubMed  Google Scholar 

  39. Romana SP, Mauchauffe M, Le Coniat M, Chumakov I, Le Paslier D, Berger R et al. The t(12;21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion. Blood 1995; 85: 3662–3670.

    CAS  PubMed  Google Scholar 

  40. Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P et al. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA 1995; 92: 4917–4921.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ichikawa M, Asai T, Saito T, Seo S, Yamazaki I, Yamagata T et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 2004; 10: 299–304.

    CAS  PubMed  Google Scholar 

  42. Niebuhr B, Kriebitzsch N, Fischer M, Behrens K, Gunther T, Alawi M et al. Runx1 is essential at two stages of early murine B-cell development. Blood 2013; 122: 413–423.

    CAS  PubMed  Google Scholar 

  43. Zelent A, Greaves M, Enver T . Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia. Oncogene 2004; 23: 4275–4283.

    CAS  PubMed  Google Scholar 

  44. Ma SK, Wan TS, Cheuk AT, Fung LF, Chan GC, Chan SY et al. Characterization of additional genetic events in childhood acute lymphoblastic leukemia with TEL/AML1 gene fusion: a molecular cytogenetics study. Leukemia 2001; 15: 1442–1447.

    CAS  PubMed  Google Scholar 

  45. Peter A, Heiden T, Taube T, Korner G, Seeger K . Interphase FISH on TEL/AML1 positive acute lymphoblastic leukemia relapses—analysis of clinical relevance of additional TEL and AML1 copy number changes. Eur J Haematol 2009; 83: 420–432.

    PubMed  Google Scholar 

  46. Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae SC, Komori T et al. Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development. Cell 2002; 111: 621–633.

    CAS  PubMed  Google Scholar 

  47. Grossmann V, Haferlach C, Weissmann S, Roller A, Schindela S, Poetzinger F et al. The molecular profile of adult T-cell acute lymphoblastic leukemia: mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL. Genes Chromosomes Cancer 2013; 52: 410–422.

    CAS  PubMed  Google Scholar 

  48. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: 157–163.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Giambra V, Jenkins CR, Wang H, Lam SH, Shevchuk OO, Nemirovsky O et al. NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-theta and reactive oxygen species. Nat Med 2012; 18: 1693–1698.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Della Gatta G, Palomero T, Perez-Garcia A, Ambesi-Impiombato A, Bansal M, Carpenter ZW et al. Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nat Med 2012; 18: 436–440.

    CAS  PubMed  Google Scholar 

  51. Kwiatkowski N, Zhang T, Rahl PB, Abraham BJ, Reddy J, Ficarro SB et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature 2014; 511: 616–620.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Wotton S, Stewart M, Blyth K, Vaillant F, Kilbey A, Neil JC et al. Proviral insertion indicates a dominant oncogenic role for Runx1/AML-1 in T-cell lymphoma. Cancer Res 2002; 62: 7181–7185.

    CAS  PubMed  Google Scholar 

  53. Chuang LS, Ito Y . RUNX3 is multifunctional in carcinogenesis of multiple solid tumors. Oncogene 2010; 29: 2605–2615.

    CAS  PubMed  Google Scholar 

  54. Ramaswamy S, Ross KN, Lander ES, Golub TR . A molecular signature of metastasis in primary solid tumors. Nat Genet 2003; 33: 49–54.

    CAS  PubMed  Google Scholar 

  55. Chimge NO, Frenkel B . The RUNX family in breast cancer: relationships with estrogen signaling. Oncogene 2013; 32: 2121–2130.

    CAS  PubMed  Google Scholar 

  56. Ellis MJ, Ding L, Shen D, Luo J, Suman VJ, Wallis JW et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 2012; 486: 353–360.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature 2012; 490: 61–70.

    Google Scholar 

  58. Kadota M, Yang HH, Gomez B, Sato M, Clifford RJ, Meerzaman D et al. Delineating genetic alterations for tumor progression in the MCF10A series of breast cancer cell lines. PLoS One 2010; 5: e9201.

    PubMed  PubMed Central  Google Scholar 

  59. Wang L, Brugge JS, Janes KA . Intersection of FOXO- and RUNX1-mediated gene expression programs in single breast epithelial cells during morphogenesis and tumor progression. Proc Natl Acad Sci USA 2011; 108: E803–E812.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Scheitz CJ, Lee TS, McDermitt DJ, Tumbar T . Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J 2012; 31: 4124–4139.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hoi CS, Lee SE, Lu SY, McDermitt DJ, Osorio KM, Piskun CM et al. Runx1 directly promotes proliferation of hair follicle stem cells and epithelial tumor formation in mouse skin. Mol Cell Biol 2010; 30: 2518–2536.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gu J, Ajani JA, Hawk ET, Ye Y, Lee JH, Bhutani MS et al. Genome-wide catalogue of chromosomal aberrations in barrett's esophagus and esophageal adenocarcinoma: a high-density single nucleotide polymorphism array analysis. Cancer Prev Res 2010; 3: 1176–1186.

    CAS  Google Scholar 

  63. Dulak AM, Schumacher SE, van Lieshout J, Imamura Y, Fox C, Shim B et al. Gastrointestinal adenocarcinomas of the esophagus, stomach, and colon exhibit distinct patterns of genome instability and oncogenesis. Cancer Res 2012; 72: 4383–4393.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Fijneman RJ, Anderson RA, Richards E, Liu J, Tijssen M, Meijer GA et al. Runx1 is a tumor suppressor gene in the mouse gastrointestinal tract. Cancer Sci 2012; 103: 593–599.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Huang SP, Lan YH, Lu TL, Pao JB, Chang TY, Lee HZ et al. Clinical significance of runt-related transcription factor 1 polymorphism in prostate cancer. BJU Int 2011; 107: 486–492.

    CAS  PubMed  Google Scholar 

  66. Slattery ML, Lundgreen A, Herrick JS, Caan BJ, Potter JD, Wolff RK . Associations between genetic variation in RUNX1, RUNX2, RUNX3, MAPK1 and eIF4E and riskof colon and rectal cancer: additional support for a TGF-beta-signaling pathway. Carcinogenesis 2011; 32: 318–326.

    CAS  PubMed  Google Scholar 

  67. Tanaka T, Kurokawa M, Ueki K, Tanaka K, Imai Y, Mitani K 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 1996; 16: 3967–3979.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhang Y, Biggs JR, Kraft AS . Phorbol ester treatment of K562 cells regulates the transcriptional activity of AML1c through phosphorylation. J Biol Chem 2004; 279: 53116–53125.

    CAS  PubMed  Google Scholar 

  69. Imai Y, Kurokawa M, Yamaguchi Y, Izutsu K, Nitta E, Mitani K et al. The corepressor mSin3A regulates phosphorylation-induced activation, intranuclear location, and stability of AML1. Mol Cell Biol 2004; 24: 1033–1043.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Aikawa Y, Nguyen LA, Isono K, Takakura N, Tagata Y, Schmitz ML et al. Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription, hematopoiesis and blood vessel formation. EMBO J 2006; 25: 3955–3965.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Wee HJ, Voon DC, Bae SC, Ito Y . PEBP2-beta/CBF-beta-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood 2008; 112: 3777–3787.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Biggs JR, Peterson LF, Zhang Y, Kraft AS, Zhang DE . AML1/RUNX1 phosphorylation by cyclin-dependent kinases regulates the degradation of AML1/RUNX1 by the anaphase-promoting complex. Mol Cell Biol 2006; 26: 7420–7429.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Guo H, Friedman AD . Phosphorylation of RUNX1 by cyclin-dependent kinase reduces direct interaction with HDAC1 and HDAC3. J Biol Chem 2011; 286: 208–215.

    CAS  PubMed  Google Scholar 

  74. Zhang L, Fried FB, Guo H, Friedman AD . Cyclin-dependent kinase phosphorylation of RUNX1/AML1 on 3 sites increases transactivation potency and stimulates cell proliferation. Blood 2008; 111: 1193–1200.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Aho TL, Sandholm J, Peltola KJ, Ito Y, Koskinen PJ . Pim-1 kinase phosphorylates RUNX family transcription factors and enhances their activity. BMC Cell Biol 2006; 7: 21.

    PubMed  PubMed Central  Google Scholar 

  76. Huang H, Woo AJ, Waldon Z, Schindler Y, Moran TB, Zhu HH et al. A Src family kinase-Shp2 axis controls RUNX1 activity in megakaryocyte and T-lymphocyte differentiation. Genes Dev 2012; 26: 1587–1601.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Yamaguchi Y, Kurokawa M, Imai Y, Izutsu K, Asai T, Ichikawa M et al. AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. J Biol Chem 2004; 279: 15630–15638.

    CAS  PubMed  Google Scholar 

  78. Wang L, Gural A, Sun XJ, Zhao X, Perna F, Huang G et al. The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science 2011; 333: 765–769.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Kitabayashi I, Aikawa Y, Nguyen LA, Yokoyama A, Ohki M . Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. EMBO J 2001; 20: 7184–7196.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Zhao X, Jankovic V, Gural A, Huang G, Pardanani A, Menendez S et al. Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity. Genes Dev 2008; 22: 640–653.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Shia WJ, Okumura AJ, Yan M, Sarkeshik A, Lo MC, Matsuura S et al. PRMT1 interacts with AML1-ETO to promote its transcriptional activation and progenitor cell proliferative potential. Blood 2012; 119: 4953–4962.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Vu LP, Perna F, Wang L, Voza F, Figueroa ME, Tempst P et al. PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep 2013; 5: 1625–1638.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Herglotz J, Kuvardina ON, Kolodziej S, Kumar A, Hussong H, Grez M et al. Histone arginine methylation keeps RUNX1 target genes in an intermediate state. Oncogene 2013; 32: 2565–2575.

    CAS  PubMed  Google Scholar 

  84. Chakraborty S, Sinha KK, Senyuk V, Nucifora G . SUV39H1 interacts with AML1 and abrogates AML1 transactivity. AML1 is methylated in vivo. Oncogene 2003; 22: 5229–5237.

    CAS  PubMed  Google Scholar 

  85. Reed-Inderbitzin E, Moreno-Miralles I, Vanden-Eynden SK, Xie J, Lutterbach B, Durst-Goodwin KL et al. RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription. Oncogene 2006; 25: 5777–5786.

    CAS  PubMed  Google Scholar 

  86. Huang G, Shigesada K, Ito K, Wee HJ, Yokomizo T, Ito Y . Dimerization with PEBP2beta protects RUNX1/AML1 from ubiquitin–proteasome-mediated degradation. EMBO J 2001; 20: 723–733.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Komeno Y, Yan M, Matsuura S, Lam K, Lo MC, Huang YJ et al. Runx1 exon 6-related alternative splicing isoforms differentially regulate hematopoiesis in mice. Blood 2014; 123: 3760–3769.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Shang Y, Zhao X, Xu X, Xin H, Li X, Zhai Y et al. CHIP functions an E3 ubiquitin ligase of Runx1. Biochem Biophys Res Commun 2009; 386: 242–246.

    CAS  PubMed  Google Scholar 

  89. Tachibana M, Tezuka C, Muroi S, Nishimoto S, Katsumoto T, Nakajima A et al. Phosphorylation of Runx1 at Ser249, Ser266, and Ser276 is dispensable for bone marrow hematopoiesis and thymocyte differentiation. Biochem Biophys Res Commun 2008; 368: 536–542.

    CAS  PubMed  Google Scholar 

  90. Yoshimi M, Goyama S, Kawazu M, Nakagawa M, Ichikawa M, Imai Y et al. Multiple phosphorylation sites are important for RUNX1 activity in early hematopoiesis and T-cell differentiation. Eur J Immunol 2012; 42: 1044–1050.

    CAS  PubMed  Google Scholar 

  91. Goyama S, Schibler J, Cunningham L, Zhang Y, Rao Y, Nishimoto N et al. Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells. J Clin Invest 2013; 123: 3876–3888.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Biggs JR, Zhang Y, Peterson LF, Garcia M, Zhang DE, Kraft AS . Phosphorylation of AML1/RUNX1 regulates its degradation and nuclear matrix association. Mol Cancer Res 2005; 3: 391–401.

    CAS  PubMed  Google Scholar 

  93. Neel BG, Speck NA . Tyrosyl phosphorylation toggles a Runx1 switch. Genes Dev 2012; 26: 1520–1526.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Gaidzik VI, Bullinger L, Schlenk RF, Zimmermann AS, Rock J, Paschka P et al. RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group. J Clin Oncol 2011; 29: 1364–1372.

    PubMed  Google Scholar 

  95. Migas A, Savva N, Mishkova O, Aleinikova OV . AML1/RUNX1 gene point mutations in childhood myeloid malignancies. Pediatr Blood Cancer 2011; 57: 583–587.

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias. Blood 1999; 93: 1817–1824.

    CAS  PubMed  Google Scholar 

  98. Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N 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 2002; 99: 1364–1372.

    CAS  PubMed  Google Scholar 

  99. Yan C, Higgins PJ . Drugging the undruggable: transcription therapy for cancer. Biochim Biophys Acta 2013; 1835: 76–85.

    CAS  PubMed  Google Scholar 

  100. Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol 2008; 10: 538–546.

    CAS  PubMed  Google Scholar 

  101. Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L et al. Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol 2008; 10: 547–555.

    CAS  PubMed  Google Scholar 

  102. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013; 369: 111–121.

    CAS  PubMed  Google Scholar 

  103. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 2008; 453: 1072–1078.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kawazu M, Asai T, Ichikawa M, Yamamoto G, Saito T, Goyama S et al. Functional domains of Runx1 are differentially required for CD4 repression, TCRbeta expression, and CD4/8 double-negative to CD4/8 double-positive transition in thymocyte development. J Immunol 2005; 174: 3526–3533.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    S Goyama, G Huang & J C Mulloy

  2. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    M Kurokawa

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  1. S Goyama
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  2. G Huang
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  3. M Kurokawa
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  4. J C Mulloy
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Correspondence to J C Mulloy.

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Goyama, S., Huang, G., Kurokawa, M. et al. Posttranslational modifications of RUNX1 as potential anticancer targets. Oncogene 34, 3483–3492 (2015). https://doi.org/10.1038/onc.2014.305

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  • DOI: https://doi.org/10.1038/onc.2014.305

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