Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The aurora kinases in cell cycle and leukemia

Oncogene volume 34, pages 537–545 (2015)Cite this article

Subjects

Abstract

The Aurora kinases, which include Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) and meiosis (AURKC). Since their discovery nearly 20 years ago, Aurora kinases have been studied extensively in cell and cancer biology. Several early studies found that Aurora kinases are amplified and overexpressed at the transcript and protein level in various malignancies, including several types of leukemia. These discoveries and others provided a rationale for the development of small-molecule inhibitors of Aurora kinases as leukemia therapies. The first generation of Aurora kinase inhibitors did not fare well in clinical trials, owing to poor efficacy and high toxicity. However, the creation of second-generation, highly selective Aurora kinase inhibitors has increased the enthusiasm for targeting these proteins in leukemia. This review will describe the functions of each Aurora kinase, summarize their involvement in leukemia and discuss inhibitor development and efficacy in leukemia clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Glover DM, Leibowitz MH, McLean DA, Parry H . Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles. Cell 1995; 81: 95–105.

    CAS  PubMed  Google Scholar 

  2. Fu J, Bian M, Liu J, Jiang Q, Zhang C . A single amino acid change converts Aurora-A into Aurora-B-like kinase in terms of partner specificity and cellular function. Proc Natl Acad Sci USA 2009; 106: 6939–6944.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Hans F, Skoufias DA, Dimitrov S, Margolis RL . Molecular distinctions between Aurora A and B: a single residue change transforms Aurora A into correctly localized and functional Aurora B. Mol Biol Cell 2009; 20: 3491–3502.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Carmena M, Earnshaw WC . The cellular geography of aurora kinases. Nat Rev Mol Cell Biol 2003; 4: 842–854.

    Article  CAS  PubMed  Google Scholar 

  5. Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B et al. A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998; 17: 3052–3065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Littlepage LE, Wu H, Andresson T, Deanehan JK, Amundadottir LT, Ruderman JV . Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A. Proc Natl Acad Sci USA 2002; 99: 15440–15445.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Walter AO, Seghezzi W, Korver W, Sheung J, Lees E . The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation. Oncogene 2000; 19: 4906–4916.

    CAS  PubMed  Google Scholar 

  8. Ferrari S, Marin O, Pagano MA, Meggio F, Hess D, El-Shemerly M et al. Aurora-A site specificity: a study with synthetic peptide substrates. Biochem J 2005; 390: 293–302.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Haydon CE, Eyers PA, Aveline-Wolf LD, Resing KA, Maller JL, Ahn NG . Identification of novel phosphorylation sites on Xenopus laevis Aurora A and analysis of phosphopeptide enrichment by immobilized metal-affinity chromatography. Mol Cell Proteomics 2003; 2: 1055–1067.

    CAS  PubMed  Google Scholar 

  10. Kimura M, Kotani S, Hattori T, Sumi N, Yoshioka T, Todokoro K et al. Cell cycle-dependent expression and spindle pole localization of a novel human protein kinase, Aik, related to Aurora of Drosophila and yeast Ipl1. J Biol Chem 1997; 272: 13766–13771.

    CAS  PubMed  Google Scholar 

  11. Kimura M, Uchida C, Takano Y, Kitagawa M, Okano Y . Cell cycle-dependent regulation of the human aurora B promoter. Biochem Biophys Res Commun 2004; 316: 930–936.

    CAS  PubMed  Google Scholar 

  12. Tanaka M, Ueda A, Kanamori H, Ideguchi H, Yang J, Kitajima S et al. Cell-cycle-dependent regulation of human aurora A transcription is mediated by periodic repression of E4TF1. J Biol Chem 2002; 277: 10719–10726.

    CAS  PubMed  Google Scholar 

  13. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 2004; 101: 6062–6067.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Taguchi S, Honda K, Sugiura K, Yamaguchi A, Furukawa K, Urano T . Degradation of human Aurora-A protein kinase is mediated by hCdh1. FEBS Lett 2002; 519: 59–65.

    CAS  PubMed  Google Scholar 

  15. Nguyen HG, Chinnappan D, Urano T, Ravid K . Mechanism of Aurora-B degradation and its dependency on intact KEN and A-boxes: identification of an aneuploidy-promoting property. Mol Cell Biol 2005; 25: 4977–4992.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Arlot-Bonnemains Y, Klotzbucher A, Giet R, Uzbekov R, Bihan R, Prigent C . Identification of a functional destruction box in the Xenopus laevis aurora-A kinase pEg2. FEBS Lett 2001; 508: 149–152.

    CAS  PubMed  Google Scholar 

  17. Crane R, Kloepfer A, Ruderman JV . Requirements for the destruction of human Aurora-A. J Cell Sci 2004; 117: 5975–5983.

    CAS  PubMed  Google Scholar 

  18. Littlepage LE, Ruderman JV . Identification of a new APC/C recognition domain, the A box, which is required for the Cdh1-dependent destruction of the kinase Aurora-A during mitotic exit. Genes Dev 2002; 16: 2274–2285.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Stewart S, Fang G . Destruction box-dependent degradation of aurora B is mediated by the anaphase-promoting complex/cyclosome and Cdh1. Cancer Res 2005; 65: 8730–8735.

    CAS  PubMed  Google Scholar 

  20. Honda K, Mihara H, Kato Y, Yamaguchi A, Tanaka H, Yasuda H et al. Degradation of human Aurora2 protein kinase by the anaphase-promoting complex-ubiquitin-proteasome pathway. Oncogene 2000; 19: 2812–2819.

    CAS  PubMed  Google Scholar 

  21. Castro A, Arlot-Bonnemains Y, Vigneron S, Labbe JC, Prigent C, Lorca T . APC/Fizzy-related targets Aurora-A kinase for proteolysis. EMBO Rep 2002; 3: 457–462.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Mao JH, Perez-Losada J, Wu D, Delrosario R, Tsunematsu R, Nakayama KI et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature 2004; 432: 775–779.

    Article  CAS  PubMed  Google Scholar 

  23. Yu X, Minter-Dykhouse K, Malureanu L, Zhao WM, Zhang D, Merkle CJ et al. Chfr is required for tumor suppression and Aurora A regulation. Nat Genet 2005; 37: 401–406.

    CAS  PubMed  Google Scholar 

  24. Lim SK, Gopalan G . Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. Biochem J 2007; 403: 119–127.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Shu F, Guo S, Dang Y, Qi M, Zhou G, Guo Z et al. Human aurora-B binds to a proteasome alpha-subunit HC8 and undergoes degradation in a proteasome-dependent manner. Mol Cell Biochem 2003; 254: 157–162.

    CAS  PubMed  Google Scholar 

  26. Adams RR, Wheatley SP, Gouldsworthy AM, Kandels-Lewis SE, Carmena M, Smythe C et al. INCENP binds the Aurora-related kinase AIRK2 and is required to target it to chromosomes, the central spindle and cleavage furrow. Curr Biol 2000; 10: 1075–1078.

    CAS  PubMed  Google Scholar 

  27. Vagnarelli P, Earnshaw WC . Chromosomal passengers: the four-dimensional regulation of mitotic events. Chromosoma 2004; 113: 211–222.

    PubMed  Google Scholar 

  28. Kaestner P, Stolz A, Bastians H . Determinants for the efficiency of anticancer drugs targeting either Aurora-A or Aurora-B kinases in human colon carcinoma cells. Mol Cancer Ther 2009; 8: 2046–2056.

    CAS  PubMed  Google Scholar 

  29. Wysong DR, Chakravarty A, Hoar K, Ecsedy JA . The inhibition of Aurora A abrogates the mitotic delay induced by microtubule perturbing agents. Cell Cycle 2009; 8: 876–888.

    CAS  PubMed  Google Scholar 

  30. Musacchio A, Hardwick KG . The spindle checkpoint: structural insights into dynamic signalling. Nat Rev Mol Cell Biol 2002; 3: 731–741.

    CAS  PubMed  Google Scholar 

  31. Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998; 20: 189–193.

    CAS  PubMed  Google Scholar 

  32. Stenoien DL, Sen S, Mancini MA, Brinkley BR . Dynamic association of a tumor amplified kinase, Aurora-A, with the centrosome and mitotic spindle. Cell Motil Cytoskeleton 2003; 55: 134–146.

    CAS  PubMed  Google Scholar 

  33. Krystyniak A, Garcia-Echeverria C, Prigent C, Ferrari S . Inhibition of Aurora A in response to DNA damage. Oncogene 2006; 25: 338–348.

    CAS  PubMed  Google Scholar 

  34. Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E et al. Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells. J Biol Chem 2003; 278: 51786–51795.

    CAS  PubMed  Google Scholar 

  35. Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M et al. Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells. Cell 2003; 114: 585–598.

    CAS  PubMed  Google Scholar 

  36. Satinover DL, Brautigan DL, Stukenberg PT . Aurora-A kinase and inhibitor-2 regulate the cyclin threshold for mitotic entry in Xenopus early embryonic cell cycles. Cell Cycle 2006; 5: 2268–2274.

    CAS  PubMed  Google Scholar 

  37. Macurek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R et al. Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature 2008; 455: 119–123.

    CAS  PubMed  Google Scholar 

  38. Seki A, Coppinger JA, Jang CY, Yates JR, Fang G . Bora and the kinase Aurora a cooperatively activate the kinase Plk1 and control mitotic entry. Science 2008; 320: 1655–1658.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Vader G, Lens SM . The Aurora kinase family in cell division and cancer. Biochim Biophys Acta 2008; 1786: 60–72.

    CAS  PubMed  Google Scholar 

  40. Barr AR, Gergely F . Aurora-A: the maker and breaker of spindle poles. J Cell Sci 2007; 120: 2987–2996.

    CAS  PubMed  Google Scholar 

  41. Bayliss R, Sardon T, Vernos I, Conti E . Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol Cell 2003; 12: 851–862.

    CAS  PubMed  Google Scholar 

  42. Lane HA, Nigg EA . Antibody microinjection reveals an essential role for human polo-like kinase 1 (Plk1) in the functional maturation of mitotic centrosomes. J Cell Biol 1996; 135: 1701–1713.

    CAS  PubMed  Google Scholar 

  43. Sunkel CE, Glover DM . polo, a mitotic mutant of Drosophila displaying abnormal spindle poles. J Cell Sci 1988; 89: 25–38.

    PubMed  Google Scholar 

  44. Petretti C, Savoian M, Montembault E, Glover DM, Prigent C, Giet R . The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation. EMBO Rep 2006; 7: 418–424.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Terada Y, Uetake Y, Kuriyama R . Interaction of Aurora-A and centrosomin at the microtubule-nucleating site in Drosophila and mammalian cells. J Cell Biol 2003; 162: 757–763.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Toji S, Yabuta N, Hosomi T, Nishihara S, Kobayashi T, Suzuki S et al. The centrosomal protein Lats2 is a phosphorylation target of Aurora-A kinase. Genes Cells 2004; 9: 383–397.

    CAS  PubMed  Google Scholar 

  47. Mori D, Yano Y, Toyo-oka K, Yoshida N, Yamada M, Muramatsu M et al. NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment. Mol Cell Biol 2007; 27: 352–367.

    CAS  PubMed  Google Scholar 

  48. Giet R, McLean D, Descamps S, Lee MJ, Raff JW, Prigent C et al. Drosophila Aurora A kinase is required to localize D-TACC to centrosomes and to regulate astral microtubules. J Cell Biol 2002; 156: 437–451.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Terada Y . Role of chromosomal passenger complex in chromosome segregation and cytokinesis. Cell Struct Funct 2001; 26: 653–657.

    CAS  PubMed  Google Scholar 

  50. Lan W, Zhang X, Kline-Smith SL, Rosasco SE, Barrett-Wilt GA, Shabanowitz J et al. Aurora B phosphorylates centromeric MCAK and regulates its localization and microtubule depolymerization activity. Curr Biol 2004; 14: 273–286.

    CAS  PubMed  Google Scholar 

  51. Ohi R, Sapra T, Howard J, Mitchison TJ . Differentiation of cytoplasmic and meiotic spindle assembly MCAK functions by Aurora B-dependent phosphorylation. Mol Biol Cell 2004; 15: 2895–2906.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Andrews PD, Ovechkina Y, Morrice N, Wagenbach M, Duncan K, Wordeman L et al. Aurora B regulates MCAK at the mitotic centromere. Dev Cell 2004; 6: 253–268.

    CAS  PubMed  Google Scholar 

  53. Honda R, Korner R, Nigg EA . Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis. Mol Biol Cell 2003; 14: 3325–3341.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yang J, Ikezoe T, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y et al. AZD1152, a novel and selective aurora B kinase inhibitor, induces growth arrest, apoptosis, and sensitization for tubulin depolymerizing agent or topoisomerase II inhibitor in human acute leukemia cells in vitro and in vivo. Blood 2007; 110: 2034–2040.

    CAS  PubMed  Google Scholar 

  55. Goto H, Yasui Y, Kawajiri A, Nigg EA, Terada Y, Tatsuka M et al. Aurora-B regulates the cleavage furrow-specific vimentin phosphorylation in the cytokinetic process. J Biol Chem 2003; 278: 8526–8530.

    CAS  PubMed  Google Scholar 

  56. Hirose K, Kawashima T, Iwamoto I, Nosaka T, Kitamura T . MgcRacGAP is involved in cytokinesis through associating with mitotic spindle and midbody. J Biol Chem 2001; 276: 5821–5828.

    CAS  PubMed  Google Scholar 

  57. Minoshima Y, Kawashima T, Hirose K, Tonozuka Y, Kawajiri A, Bao YC et al. Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis. Dev Cell 2003; 4: 549–560.

    CAS  PubMed  Google Scholar 

  58. Kimura M, Matsuda Y, Yoshioka T, Okano Y . Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem 1999; 274: 7334–7340.

    CAS  PubMed  Google Scholar 

  59. Kimura M, Matsuda Y, Yoshioka T, Sumi N, Okano Y . Identification and characterization of STK12/Aik2: a human gene related to aurora of Drosophila and yeast IPL1. Cytogenet Cell Genet 1998; 82: 147–152.

    CAS  PubMed  Google Scholar 

  60. Li X, Sakashita G, Matsuzaki H, Sugimoto K, Kimura K, Hanaoka F et al. Direct association with inner centromere protein (INCENP) activates the novel chromosomal passenger protein, Aurora-C. J Biol Chem 2004; 279: 47201–47211.

    CAS  PubMed  Google Scholar 

  61. Sasai K, Katayama H, Stenoien DL, Fujii S, Honda R, Kimura M et al. Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells. Cell Motil Cytoskeleton 2004; 59: 249–263.

    CAS  PubMed  Google Scholar 

  62. Yan X, Cao L, Li Q, Wu Y, Zhang H, Saiyin H et al. Aurora C is directly associated with Survivin and required for cytokinesis. Genes Cells 2005; 10: 617–626.

    CAS  PubMed  Google Scholar 

  63. Kimmins S, Crosio C, Kotaja N, Hirayama J, Monaco L, Hoog C et al. Differential functions of the Aurora-B and Aurora-C kinases in mammalian spermatogenesis. Mol Endocrinol 2007; 21: 726–739.

    CAS  PubMed  Google Scholar 

  64. Dieterich K, Soto Rifo R, Faure AK, Hennebicq S, Ben Amar B, Zahi M et al. Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility. Nat Genet 2007; 39: 661–665.

    CAS  PubMed  Google Scholar 

  65. Peset I, Seiler J, Sardon T, Bejarano LA, Rybina S, Vernos I . Function and regulation of Maskin, a TACC family protein, in microtubule growth during mitosis. J Cell Biol 2005; 170: 1057–1066.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Liu Q, Ruderman JV . Aurora A, mitotic entry, and spindle bipolarity. Proc Natl Acad Sci USA 2006; 103: 5811–5816.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Marumoto T, Hirota T, Morisaki T, Kunitoku N, Zhang D, Ichikawa Y et al. Roles of aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes Cells 2002; 7: 1173–1182.

    CAS  PubMed  Google Scholar 

  68. Hachet V, Canard C, Gonczy P . Centrosomes promote timely mitotic entry in C. elegans embryos. Dev Cell 2007; 12: 531–541.

    CAS  PubMed  Google Scholar 

  69. Portier N, Audhya A, Maddox PS, Green RA, Dammermann A, Desai A et al. A microtubule-independent role for centrosomes and aurora a in nuclear envelope breakdown. Dev Cell 2007; 12: 515–529.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Schumacher JM, Ashcroft N, Donovan PJ, Golden A . A highly conserved centrosomal kinase, AIR-1, is required for accurate cell cycle progression and segregation of developmental factors in Caenorhabditis elegans embryos. Development 1998; 125: 4391–4402.

    CAS  PubMed  Google Scholar 

  71. Lu LY, Wood JL, Ye L, Minter-Dykhouse K, Saunders TL, Yu X et al. Aurora A is essential for early embryonic development and tumor suppression. J Biol Chem 2008; 283: 31785–31790.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Cowley DO, Rivera-Perez JA, Schliekelman M, He YJ, Oliver TG, Lu L et al. Aurora-A kinase is essential for bipolar spindle formation and early development. Mol Cell Biol 2009; 29: 1059–1071.

    CAS  PubMed  Google Scholar 

  73. Yoon Y, Cowley DO, Gallant J, Jones SN, Van Dyke T, Rivera-Perez JA . Conditional Aurora A deficiency differentially affects early mouse embryo patterning. Dev Biol 2012; 371: 77–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Hegarat N, Smith E, Nayak G, Takeda S, Eyers PA, Hochegger H . Aurora A and Aurora B jointly coordinate chromosome segregation and anaphase microtubule dynamics. J Cell Biol 2011; 195: 1103–1113.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Giet R, Glover DM . Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J Cell Biol 2001; 152: 669–682.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Fernandez-Miranda G, Trakala M, Martin J, Escobar B, Gonzalez A, Ghyselinck NB et al. Genetic disruption of aurora B uncovers an essential role for aurora C during early mammalian development. Development 2011; 138: 2661–2672.

    CAS  PubMed  Google Scholar 

  77. Yang J, Ikezoe T, Nishioka C, Nobumoto A, Udaka K, Yokoyama A . CD34 /CD38 acute myelogenous leukemia cells aberrantly express Aurora kinase A. Int J Cancer 2013; 133: 2706–2719.

    CAS  PubMed  Google Scholar 

  78. Ye D, Garcia-Manero G, Kantarjian HM, Xiao L, Vadhan-Raj S, Fernandez MH et al. Analysis of Aurora kinase A expression in CD34(+) blast cells isolated from patients with myelodysplastic syndromes and acute myeloid leukemia. J Hematop 2009; 2: 2–8.

    PubMed  Google Scholar 

  79. Gu J, Gong Y, Huang M, Lu C, Spitz MR, Wu X . Polymorphisms of STK15 (Aurora-A) gene and lung cancer risk in Caucasians. Carcinogenesis 2007; 28: 350–355.

    CAS  PubMed  Google Scholar 

  80. Sakakura C, Hagiwara A, Yasuoka R, Fujita Y, Nakanishi M, Masuda K et al. Tumour-amplified kinase BTAK is amplified and overexpressed in gastric cancers with possible involvement in aneuploid formation. Br J Cancer 2001; 84: 824–831.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Anand S, Penrhyn-Lowe S, Venkitaraman AR . AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 2003; 3: 51–62.

    CAS  PubMed  Google Scholar 

  82. Tatsuka M, Sato S, Kitajima S, Suto S, Kawai H, Miyauchi M et al. Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene 2005; 24: 1122–1127.

    CAS  PubMed  Google Scholar 

  83. Vernos I, Karsenti E . Chromosomes take the lead in spindle assembly. Trends Cell Biol 1995; 5: 297–301.

    CAS  PubMed  Google Scholar 

  84. Nigg EA . Mitotic kinases as regulators of cell division and its checkpoints. Nat Rev Mol Cell Biol 2001; 2: 21–32.

    CAS  PubMed  Google Scholar 

  85. Ke YW, Dou Z, Zhang J, Yao XB . Function and regulation of Aurora/Ipl1p kinase family in cell division. Cell Res 2003; 13: 69–81.

    CAS  PubMed  Google Scholar 

  86. Liu Q, Kaneko S, Yang L, Feldman RI, Nicosia SV, Chen J et al. Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215. J Biol Chem 2004; 279: 52175–52182.

    CAS  PubMed  Google Scholar 

  87. Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F et al. Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 2004; 36: 55–62.

    CAS  PubMed  Google Scholar 

  88. Mao JH, Wu D, Perez-Losada J, Jiang T, Li Q, Neve RM et al. Crosstalk between Aurora-A and p53: frequent deletion or downregulation of Aurora-A in tumors from p53 null mice. Cancer Cell 2007; 11: 161–173.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Nair JS, Ho AL, Schwartz GK . The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent. Cell Cycle 2012; 11: 807–817.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Dennis M, Davies M, Oliver S, D'Souza R, Pike L, Stockman P . Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia. Cancer Chemother Pharmacol 2012; 70: 461–469.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Nguyen HG, Makitalo M, Yang D, Chinnappan D, St Hilaire C, Ravid K . Deregulated Aurora-B induced tetraploidy promotes tumorigenesis. FASEB J 2009; 23: 2741–2748.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ota T, Suto S, Katayama H, Han ZB, Suzuki F, Maeda M et al. Increased mitotic phosphorylation of histone H3 attributable to AIM-1/Aurora-B overexpression contributes to chromosome number instability. Cancer Res 2002; 62: 5168–5177.

    CAS  PubMed  Google Scholar 

  93. Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D . Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005; 437: 1043–1047.

    CAS  PubMed  Google Scholar 

  94. Zekri A, Lesan V, Ghaffari SH, Tabrizi MH, Modarressi MH . Gene amplification and overexpression of Aurora-C in breast and prostate cancer cell lines. Oncol Res 2012; 20: 241–250.

    CAS  PubMed  Google Scholar 

  95. Tsou JH, Chang KC, Chang-Liao PY, Yang ST, Lee CT, Chen YP et al. Aberrantly expressed AURKC enhances the transformation and tumourigenicity of epithelial cells. J Pathol 2011; 225: 243–254.

    CAS  PubMed  Google Scholar 

  96. Khan J, Ezan F, Cremet JY, Fautrel A, Gilot D, Lambert M et al. Overexpression of active Aurora-C kinase results in cell transformation and tumour formation. PLoS One 2011; 6: e26512.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Vitrat N, Cohen-Solal K, Pique C, Le Couedic JP, Norol F, Larsen AK et al. Endomitosis of human megakaryocytes are due to abortive mitosis. Blood 1998; 91: 3711–3723.

    CAS  PubMed  Google Scholar 

  98. Geddis AE, Fox NE, Tkachenko E, Kaushansky K . Endomitotic megakaryocytes that form a bipolar spindle exhibit cleavage furrow ingression followed by furrow regression. Cell Cycle 2007; 6: 455–460.

    CAS  PubMed  Google Scholar 

  99. Lordier L, Jalil A, Aurade F, Larbret F, Larghero J, Debili N et al. Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling. Blood 2008; 112: 3164–3174.

    CAS  PubMed  Google Scholar 

  100. Geddis AE, Kaushansky K . Endomitotic megakaryocytes form a midzone in anaphase but have a deficiency in cleavage furrow formation. Cell Cycle 2006; 5: 538–545.

    CAS  PubMed  Google Scholar 

  101. Zhang Y, Sun S, Chen WC, Kaluzhny Y, Chinnappan D, Yu G et al. Repression of AIM-1 kinase mRNA as part of a program of genes regulated by Mpl ligand. Biochem Biophys Res Commun 2001; 282: 844–849.

    CAS  PubMed  Google Scholar 

  102. Kawasaki A, Matsumura I, Miyagawa J, Ezoe S, Tanaka H, Terada Y et al. Downregulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells. J Cell Biol 2001; 152: 275–287.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang Y, Nagata Y, Yu G, Nguyen HG, Jones MR, Toselli P et al. Aberrant quantity and localization of Aurora-B/AIM-1 and survivin during megakaryocyte polyploidization and the consequences of Aurora-B/AIM-1-deregulated expression. Blood 2004; 103: 3717–3726.

    CAS  PubMed  Google Scholar 

  104. Geddis AE, Kaushansky K . Megakaryocytes express functional Aurora-B kinase in endomitosis. Blood 2004; 104: 1017–1024.

    CAS  PubMed  Google Scholar 

  105. Lordier L, Chang Y, Jalil A, Aurade F, Garcon L, Lecluse Y et al. Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process. Blood 2010; 116: 2345–2355.

    CAS  PubMed  Google Scholar 

  106. Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 2002; 32: 148–152.

    CAS  PubMed  Google Scholar 

  107. Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet 2013.

  108. Nikolaev SI, Santoni F, Vannier A, Falconnet E, Giarin E, Basso G et al. Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome. Blood 2013; 122: 554–561.

    CAS  PubMed  Google Scholar 

  109. de Rooij JD, Hollink IH, Arentsen-Peters ST, van Galen JF, Berna Beverloo H, Baruchel A et al. NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia 2013; 27: 2280–2288.

    CAS  PubMed  Google Scholar 

  110. Gruber TA, Larson Gedman A, Zhang J, Koss CS, Marada S, Ta HQ et al. An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell 2012; 22: 683–697.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Thiollier C, Lopez CK, Gerby B, Ignacimouttou C, Poglio S, Duffourd Y et al. Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. J Exp Med 2012; 209: 2017–2031.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Mercher T, Raffel GD, Moore SA, Cornejo MG, Baudry-Bluteau D, Cagnard N et al. The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J Clin Invest 2009; 119: 852–864.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Radtke I, Mullighan CG, Ishii M, Su X, Cheng J, Ma J et al. Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proc Natl Acad Sci USA 2009; 106: 12944–12949.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Wen Q, Goldenson B, Crispino JD . Normal and malignant megakaryopoiesis. Expert Rev Mol Med 2011; 13: e32.

    PubMed  PubMed Central  Google Scholar 

  115. Malinge S, Ragu C, Della-Valle V, Pisani D, Constantinescu SN, Perez C et al. Activating mutations in human acute megakaryoblastic leukemia. Blood 2008; 112: 4220–4226.

    CAS  PubMed  Google Scholar 

  116. Walters DK, Mercher T, Gu TL, O'Hare T, Tyner JW, Loriaux M et al. Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 2006; 10: 65–75.

    CAS  PubMed  Google Scholar 

  117. Kiyoi H, Yamaji S, Kojima S, Naoe T . JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults. Leukemia 2007; 21: 574–576.

    CAS  PubMed  Google Scholar 

  118. Leow S, Kham SK, Ariffin H, Quah TC, Yeoh AE . FLT3 mutation and expression did not adversely affect clinical outcome of childhood acute leukaemia: a study of 531 Southeast Asian children by the Ma-Spore study group. Hematol Oncol 2011; 29: 211–219.

    CAS  PubMed  Google Scholar 

  119. Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood 2005; 106: 3370–3373.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Steensma DP, McClure RF, Karp JE, Tefferi A, Lasho TL, Powell HL et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia 2006; 20: 971–978.

    CAS  PubMed  Google Scholar 

  121. Wen Q, Goldenson B, Silver SJ, Schenone M, Dancik V, Huang Z et al. Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell 2012; 150: 575–589.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Lugo TG, Pendergast AM, Muller AJ, Witte ON . Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science 1990; 247: 1079–1082.

    CAS  PubMed  Google Scholar 

  123. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    CAS  PubMed  Google Scholar 

  124. Weinstein IB . Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 2002; 297: 63–64.

    CAS  PubMed  Google Scholar 

  125. Lens SM, Voest EE, Medema RH . Shared and separate functions of polo-like kinases and aurora kinases in cancer. Nat Rev Cancer 2010; 10: 825–841.

    CAS  PubMed  Google Scholar 

  126. Tallman MS, Nabhan C, Feusner JH, Rowe JM . Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002; 99: 759–767.

    CAS  PubMed  Google Scholar 

  127. Breitman TR, Collins SJ, Keene BR . Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 1981; 57: 1000–1004.

    CAS  PubMed  Google Scholar 

  128. Kollareddy M, Zheleva D, Dzubak P, Brahmkshatriya PS, Lepsik M, Hajduch M . Aurora kinase inhibitors: Progress towards the clinic. Invest New Drugs 2012; 30: 2411–2432.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Ikezoe T, Yang J, Nishioka C, Tasaka T, Taniguchi A, Kuwayama Y et al. A novel treatment strategy targeting Aurora kinases in acute myelogenous leukemia. Mol Cancer Ther 2007; 6: 1851–1857.

    CAS  PubMed  Google Scholar 

  130. Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J et al. Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity. J Med Chem 2009; 52: 379–388.

    CAS  PubMed  Google Scholar 

  131. Okabe S, Tauchi T, Tanaka Y, Kimura S, Maekawa T, Ohyashiki K . Activity of histone deacetylase inhibitors and an Aurora kinase inhibitor in BCR-ABL-expressing leukemia cells: combination of HDAC and Aurora inhibitors in BCR-ABL-expressing cells. Cancer Cell Int 2013; 13: 32.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Yuan H, Wang Z, Zhang H, Roth M, Bhatia R, Chen WY . Overcoming CML acquired resistance by specific inhibition of Aurora A kinase in the KCL-22 cell model. Carcinogenesis 2012; 33: 285–293.

    CAS  PubMed  Google Scholar 

  133. Giles FJ, Cortes J, Jones D, Bergstrom D, Kantarjian H, Freedman SJ . MK-0457 a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007; 109: 500–502.

    CAS  PubMed  Google Scholar 

  134. Jayanthan A, Cooper TM, Hoeksema KA, Lotfi S, Woldum E, Lewis VA et al. Occurrence and modulation of therapeutic targets of Aurora kinase inhibition in pediatric acute leukemia cells. Leuk Lymphoma 2013; 54: 1505–1516.

    CAS  PubMed  Google Scholar 

  135. Qi W, Liu X, Cooke LS, Persky DO, Miller TP, Squires M et al. AT9283, a novel aurora kinase inhibitor, suppresses tumor growth in aggressive B-cell lymphomas. Int J Cancer 2012; 130: 2997–3005.

    CAS  PubMed  Google Scholar 

  136. Shah M, Gallipoli P, Lyons J, Holyoake T, Jorgensen H . Effects of the novel aurora kinase/JAK inhibitor, AT9283 and imatinib on Philadelphia positive cells in vitro. Blood Cells Mol Dis 2012; 48: 199–201.

    CAS  PubMed  Google Scholar 

  137. Graux C, Sonet A, Maertens J, Duyster J, Greiner J, Chalandon Y et al. A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies. Leuk Res 2013; 37: 1100–1106.

    CAS  PubMed  Google Scholar 

  138. Raymond E, Alexandre J, Faivre S, Goldwasser F, Besse-Hammer T, Gianella-Borradori A et al A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors. Invest New Drugs 2013; 32: 94–103.

    PubMed  Google Scholar 

  139. Mita M, Gordon M, Rejeb N, Gianella-Borradori A, Jego V, Mita A et al A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors. Target Oncol (e-pub ahead of print 6 July 2013).

    PubMed  Google Scholar 

  140. Manfredi MG, Ecsedy JA, Chakravarty A, Silverman L, Zhang M, Hoar KM et al. Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays. Clin Cancer Res 2011; 17: 7614–7624.

    CAS  PubMed  Google Scholar 

  141. Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W et al. Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci USA 2007; 104: 4106–4111.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Hoar K, Chakravarty A, Rabino C, Wysong D, Bowman D, Roy N et al. MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy. Mol Cell Biol 2007; 27: 4513–4525.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Kelly KR, Nawrocki ST, Espitia CM, Zhang M, Yang JJ, Padmanabhan S et al. Targeting Aurora A kinase activity with the investigational agent alisertib increases the efficacy of cytarabine through a FOXO-dependent mechanism. Int J Cancer 2012; 131: 2693–2703.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Goldberg SLFP, Craig MD, Gyan E, Lister J, Kassis J, Pigneux A et al. Phase 2 study of MLN8237, an investigational Aurora A kinase (AAK) inhibitor in patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS). Blood 2010; 116: 3273.

    Google Scholar 

  145. Kelly KR, Ecsedy J, Medina E, Mahalingam D, Padmanabhan S, Nawrocki ST et al. The novel Aurora A kinase inhibitor MLN8237 is active in resistant chronic myeloid leukaemia and significantly increases the efficacy of nilotinib. J Cell Mol Med 2011; 15: 2057–2070.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Fei F, Lim M, Schmidhuber S, Moll J, Groffen J, Heisterkamp N . Treatment of human pre-B acute lymphoblastic leukemia with the Aurora kinase inhibitor PHA-739358 (Danusertib). Mol Cancer 2012; 11: 42.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Walsby E, Walsh V, Pepper C, Burnett A, Mills K . Effects of the aurora kinase inhibitors AZD1152-HQPA and ZM447439 on growth arrest and polyploidy in acute myeloid leukemia cell lines and primary blasts. Haematologica 2008; 93: 662–669.

    CAS  PubMed  Google Scholar 

  148. Oke A, Pearce D, Wilkinson RW, Crafter C, Odedra R, Cavenagh J et al. AZD1152 rapidly and negatively affects the growth and survival of human acute myeloid leukemia cells in vitro and in vivo. Cancer Res 2009; 69: 4150–4158.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Hartsink-Segers SA, Zwaan CM, Exalto C, Luijendijk MW, Calvert VS, Petricoin EF et al. Aurora kinases in childhood acute leukemia: the promise of aurora B as therapeutic target. Leukemia 2013; 27: 560–568.

    CAS  PubMed  Google Scholar 

  150. Yamauchi T, Uzui K, Shigemi H, Negoro E, Yoshida A, Ueda T . Aurora B inhibitor barasertib and cytarabine exert a greater-than-additive cytotoxicity in acute myeloid leukemia cells. Cancer Sci 2013; 104: 926–933.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Lowenberg B, Muus P, Ossenkoppele G, Rousselot P, Cahn JY, Ifrah N et al. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood 2011; 118: 6030–6036.

    PubMed  PubMed Central  Google Scholar 

  152. Tsuboi K, Yokozawa T, Sakura T, Watanabe T, Fujisawa S, Yamauchi T et al. A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia. Leuk Res 2011; 35: 1384–1389.

    CAS  PubMed  Google Scholar 

  153. Kantarjian HM, Martinelli G, Jabbour EJ, Quintas-Cardama A, Ando K, Bay JO et al. Stage I of a phase 2 study assessing the efficacy, safety, and tolerability of barasertib (AZD1152) versus low-dose cytosine arabinoside in elderly patients with acute myeloid leukemia. Cancer 2013; 119: 2611–2619.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to those whose work could not be discussed due to space limitations. This review was supported by grants from the NIH (R01s CA101774 and HL112792), the Samuel Waxman Cancer Research Foundation and the Leukemia and Lymphoma Society. BG is supported by the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Sciences (NCATS) (TL1R000108).

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Northwestern University, Chicago,, IL, USA

    B Goldenson & J D Crispino

Authors
  1. B Goldenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J D Crispino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J D Crispino.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goldenson, B., Crispino, J. The aurora kinases in cell cycle and leukemia. Oncogene 34, 537–545 (2015). https://doi.org/10.1038/onc.2014.14

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.14

This article is cited by

Search

Advanced search

Quick links