Advertisement

New insights into the biology of acute myeloid leukemia with mutated NPM1

  • Lorenzo Brunetti
  • Michael C. Gundry
  • Margaret A. GoodellEmail author
Progress in Hematology Epigenetic abnormalities and therapies for hematological malignancies
  • 170 Downloads

Abstract

Acute myeloid leukemia (AML), the most common acute leukemia in adults, increases exponentially with age. While a number of recent advances have improved treatment, high cure rates have not yet been achieved. Nucleophosmin (NPM1) is found mutated in nearly one-third of newly diagnosed cases and leads to NPM1 protein that is mislocalized to the cytoplasm instead of the nucleolus. If the mechanistic basis through which this mislocalization leads to malignancy could be revealed, this AML subtype may be targetable with new drugs. Here, we review the structure and functions of the normal and mutant forms of nucleophosmin. We discuss several recent studies that have shed light on the pathophysiology of NPM1 mutations. We discuss the importance of HOX gene misregulation in NPM1-mutated leukemias, as well as evidence for the reliance of mutated NPM1 on its continued nuclear export. Together, these aspects, as well as new tools to manipulate and study NPM1, open the door to new therapeutic strategies that may ultimately improve treatment of this common subtype of AML.

Keywords

NPM1 B23 HOX Acute myeloid leukemia AML XPO1 

Notes

Acknowledgements

This work has been supported by the NIH (DK092883, CA183252) and the Samuel Waxman Cancer Research Foundation.

References

  1. 1.
    Döhner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:1136–52.  https://doi.org/10.1056/NEJMra1406184.CrossRefPubMedGoogle Scholar
  2. 2.
    Deschler B, Lubbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer. 2006;107:2099–107.  https://doi.org/10.1002/cncr.22233.CrossRefPubMedGoogle Scholar
  3. 3.
    Network C. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.  https://doi.org/10.1056/NEJMoa1301689.CrossRefGoogle Scholar
  4. 4.
    Papaemmanuil E, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374:2209–21.  https://doi.org/10.1056/NEJMoa1516192.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Falini B, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254–66.  https://doi.org/10.1056/NEJMoa041974.CrossRefPubMedGoogle Scholar
  6. 6.
    Heath EM, et al. Biological and clinical consequences of NPM1 mutations in AML. Leukemia. 2017;31:798–807.  https://doi.org/10.1038/leu.2017.30.CrossRefPubMedGoogle Scholar
  7. 7.
    Swerdlow SH. International Agency for Research on Cancer & World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues, 4th edn. International Agency for Research on Cancer; 2008. ISBN-10: 9283224310Google Scholar
  8. 8.
    Borer RA, Lehner CF, Eppenberger HM, Nigg EA. Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell. 1989;56:379–90.CrossRefPubMedGoogle Scholar
  9. 9.
    Olson MOJ. The nucleolus. New York: Springer; 2011.CrossRefGoogle Scholar
  10. 10.
    Namboodiri VM, Akey IV, Schmidt-Zachmann MS, Head JF, Akey CW. The structure and function of Xenopus NO38-core, a histone chaperone in the nucleolus. Structure. 2004;12:2149–60.  https://doi.org/10.1016/j.str.2004.09.017.CrossRefPubMedGoogle Scholar
  11. 11.
    Lee HH, et al. Crystal structure of human nucleophosmin-core reveals plasticity of the pentamer–pentamer interface. Proteins. 2007;69:672–8.  https://doi.org/10.1002/prot.21504.CrossRefPubMedGoogle Scholar
  12. 12.
    Szebeni A, Olson MO. Nucleolar protein B23 has molecular chaperone activities. Protein Sci. 1999;8:905–12.  https://doi.org/10.1110/ps.8.4.905.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Maggi LB Jr, et al. Nucleophosmin serves as a rate-limiting nuclear export chaperone for the Mammalian ribosome. Mol Cell Biol. 2008;28:7050–65.  https://doi.org/10.1128/MCB.01548-07.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Wang W, Budhu A, Forgues M, Wang XW. Temporal and spatial control of nucleophosmin by the Ran-Crm1 complex in centrosome duplication. Nat Cell Biol. 2005;7:823–30.  https://doi.org/10.1038/ncb1282.CrossRefPubMedGoogle Scholar
  15. 15.
    Swaminathan V, Kishore AH, Febitha KK, Kundu TK. Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol Cell Biol. 2005;25:7534–45.  https://doi.org/10.1128/MCB.25.17.7534-7545.2005.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gadad SS, et al. The multifunctional protein nucleophosmin (NPM1) is a human linker histone H1 chaperone. Biochemistry. 2011;50:2780–9.  https://doi.org/10.1021/bi101835j.CrossRefPubMedGoogle Scholar
  17. 17.
    Mitrea DM, et al. Nucleophosmin integrates within the nucleolus via multi-modal interactions with proteins displaying R-rich linear motifs and rRNA. Elife; 2016.  https://doi.org/10.7554/eLife.13571 (2016).
  18. 18.
    Mitrea DM, et al. Self-interaction of NPM1 modulates multiple mechanisms of liquid–liquid phase separation. Nat Commun. 2018;9:842.  https://doi.org/10.1038/s41467-018-03255-3.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hingorani K, Szebeni A, Olson MO. Mapping the functional domains of nucleolar protein B23. J Biol Chem. 2000;275:24451–7.  https://doi.org/10.1074/jbc.M003278200.CrossRefPubMedGoogle Scholar
  20. 20.
    Colombo E, Marine J-C, Danovi D, Falini B, Pelicci P. Nucleophosmin regulates the stability and transcriptional activity of p53. Nat Cell Biol. 2002;4:529–33.  https://doi.org/10.1038/ncb814.CrossRefPubMedGoogle Scholar
  21. 21.
    Chang JH, Olson MO. A single gene codes for two forms of rat nucleolar protein B23 mRNA. J Biol Chem. 1989;264:11732–7.PubMedGoogle Scholar
  22. 22.
    Nishimura Y, Ohkubo T, Furuichi Y, Umekawa H. Tryptophans 286 and 288 in the C-terminal region of protein B23.1 are important for its nucleolar localization. Biosci Biotechnol Biochem. 2002;66:2239–42.  https://doi.org/10.1271/bbb.66.2239.CrossRefPubMedGoogle Scholar
  23. 23.
    Grummitt CG, Townsley FM, Johnson CM, Warren AJ, Bycroft M. Structural consequences of nucleophosmin mutations in acute myeloid leukemia. J Biol Chem. 2008;283:23326–32.  https://doi.org/10.1074/jbc.M801706200.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Dingwall C, Laskey RA. Nucleoplasmin: the archetypal molecular chaperone. Semin Cell Biol. 1990;1:11–7.PubMedGoogle Scholar
  25. 25.
    Okuwaki M, Matsumoto K, Tsujimoto M, Nagata K. Function of nucleophosmin/B23, a nucleolar acidic protein, as a histone chaperone. FEBS Lett. 2001;506:272–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Shandilya J, et al. Acetylated NPM1 localizes in the nucleoplasm and regulates transcriptional activation of genes implicated in oral cancer manifestation. Mol Cell Biol. 2009;29:5115–27.  https://doi.org/10.1128/MCB.01969-08.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Malik-Soni N, Frappier L. Nucleophosmin contributes to the transcriptional activation function of the Epstein-Barr virus EBNA1 protein. J Virol. 2014;88:2323–6.  https://doi.org/10.1128/JVI.02521-13.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Holmberg Olausson K, Nister M, Lindstrom MS. Loss of nucleolar histone chaperone NPM1 triggers rearrangement of heterochromatin and synergizes with a deficiency in DNA methyltransferase DNMT3A to drive ribosomal DNA transcription. J Biol Chem. 2014;289:34601–19.  https://doi.org/10.1074/jbc.M114.569244.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Liu H, et al. Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation. EMBO Rep. 2007;8:394–400.  https://doi.org/10.1038/sj.embor.7400909.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yu Y, et al. Nucleophosmin is essential for ribosomal protein L5 nuclear export. Mol Cell Biol. 2006;26:3798–809.  https://doi.org/10.1128/MCB.26.10.3798-3809.2006.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Pelletier CL, et al. TSC1 sets the rate of ribosome export and protein synthesis through nucleophosmin translation. Cancer Res. 2007;67:1609–17.  https://doi.org/10.1158/0008-5472.CAN-06-2875.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lindström MS, Zhang Y, Ribosomal Protein S. 9 Is a novel B23/NPM-binding protein required for normal cell proliferation. J Biol Chem. 2008;283:15568–76.  https://doi.org/10.1074/jbc.M801151200.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Savkur RS, Olson MO. Preferential cleavage in pre-ribosomal RNA by protein B23 endoribonuclease. Nucleic Acids Res. 1998;26:4508–15.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Pan WA, et al. The RNA recognition motif of NIFK is required for rRNA maturation during cell cycle progression. RNA Biol. 2015;12:255–67.  https://doi.org/10.1080/15476286.2015.1017221.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Itahana K, et al. Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell. 2003;12:1151–64.CrossRefPubMedGoogle Scholar
  36. 36.
    Grisendi S, et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature. 2005;437:147–53.  https://doi.org/10.1038/nature03915.CrossRefPubMedGoogle Scholar
  37. 37.
    Colombo E, et al. Nucleophosmin is required for DNA integrity and p19Arf protein stability. Mol Cell Biol. 2005;25:8874–86.  https://doi.org/10.1128/MCB.25.20.8874-8886.2005.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mukhopadhyay A, et al. 14-3-3gamma prevents centrosome amplification and neoplastic progression. Sci Rep. 2016;6:26580.  https://doi.org/10.1038/srep26580.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Kuo ML, den Besten W, Thomas MC, Sherr CJ. Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3. Cell Cycle. 2008;7:3378–87.  https://doi.org/10.4161/cc.7.21.6930.CrossRefPubMedGoogle Scholar
  40. 40.
    Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ. N-terminal polyubiquitination and degradation of the Arf tumor suppressor. Genes Dev. 2004;18:1862–74.  https://doi.org/10.1101/gad.1213904.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Sherr CJ. The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol. 2001;2:731–7.  https://doi.org/10.1038/35096061.CrossRefPubMedGoogle Scholar
  42. 42.
    Rubbi CP, Milner J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 2003.  https://doi.org/10.1093/emboj/cdg579.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Falini B, Brunetti L, Martelli MP. Dactinomycin in NPM1-mutated acute myeloid leukemia. N Engl J Med. 2015;373:1180–2.  https://doi.org/10.1056/NEJMc1509584.CrossRefPubMedGoogle Scholar
  44. 44.
    Brunetti L, Gundry MC, Goodell MA. DNMT3A in leukemia. Cold Spring Harb Perspect Med; 2017.  https://doi.org/10.1101/cshperspect.a030320.CrossRefPubMedGoogle Scholar
  45. 45.
    Guryanova OA, et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med. 2016;22:1488–95.  https://doi.org/10.1038/nm.4210.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Falini B, Mason DY. Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. Blood. 2002;99:409–26.CrossRefPubMedGoogle Scholar
  47. 47.
    Falini B, et al. Translocations and mutations involving the nucleophosmin (NPM1) gene in lymphomas and leukemias. Haematologica. 2007;92:519–32.CrossRefPubMedGoogle Scholar
  48. 48.
    Falini B, et al. Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia. 2009;23:1731–43.  https://doi.org/10.1038/leu.2009.124.CrossRefPubMedGoogle Scholar
  49. 49.
    Falini B, et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc + AML. Blood. 2006;107:4514–23.  https://doi.org/10.1182/blood-2005-11-4745.CrossRefPubMedGoogle Scholar
  50. 50.
    Sportoletti P, et al. Npm1 is a haploinsufficient suppressor of myeloid and lymphoid malignancies in the mouse. Blood. 2008;111:3859–62.  https://doi.org/10.1182/blood-2007-06-098251.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Colombo E, et al. Delocalization and destabilization of the Arf tumor suppressor by the leukemia-associated NPM mutant. Cancer Res. 2006;66:3044–50.  https://doi.org/10.1158/0008-5472.CAN-05-2378.CrossRefPubMedGoogle Scholar
  52. 52.
    Bonetti P, et al. Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma. J Cell Biol. 2008;182:19–26.  https://doi.org/10.1083/jcb.200711040.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Cheng K, et al. The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood. 2010;115:3341–5.  https://doi.org/10.1182/blood-2009-03-208587.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Sportoletti P, et al. The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model. Blood. 2013;121:3447–58.  https://doi.org/10.1182/blood-2012-08-449553.CrossRefPubMedGoogle Scholar
  55. 55.
    Vassiliou GS, et al. Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice. Nat Genet. 2011;43:470–5.  https://doi.org/10.1038/ng.796.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Sportoletti P, et al. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications. Leukemia. 2015;29:269–78.  https://doi.org/10.1038/leu.2014.257.CrossRefPubMedGoogle Scholar
  57. 57.
    Dovey OM, et al. Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia. Blood. 2017.  https://doi.org/10.1182/blood-2017-01-760595.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Alcalay M, et al. Acute myeloid leukemia bearing cytoplasmic nucleophosmin (NPMc + AML) shows a distinct gene expression profile characterized by up-regulation of genes involved in stem-cell maintenance. Blood. 2005;106:899–902.  https://doi.org/10.1182/blood-2005-02-0560.CrossRefPubMedGoogle Scholar
  59. 59.
    Verhaak RG, et al. Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood. 2005;106:3747–54.  https://doi.org/10.1182/blood-2005-05-2168.CrossRefPubMedGoogle Scholar
  60. 60.
    Mallo M, Alonso CR. The regulation of Hox gene expression during animal development. Development. 2013;140:3951–63.  https://doi.org/10.1242/dev.068346.CrossRefPubMedGoogle Scholar
  61. 61.
    Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet. 2005;6:893–904.  https://doi.org/10.1038/nrg1726.CrossRefPubMedGoogle Scholar
  62. 62.
    Argiropoulos B, Humphries RK. Hox genes in hematopoiesis and leukemogenesis. Oncogene. 2007;26:6766–76.  https://doi.org/10.1038/sj.onc.1210760.CrossRefPubMedGoogle Scholar
  63. 63.
    Spencer DH, et al. Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells. Leukemia. 2015;29:1279–89.  https://doi.org/10.1038/leu.2015.6.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Brunetti L, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018;34(499):499–512.  https://doi.org/10.1016/j.ccell.2018.08.005. e.CrossRefPubMedGoogle Scholar
  65. 65.
    Cao K, et al. SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression. Genes Dev. 2017;31:787–801.  https://doi.org/10.1101/gad.294744.116.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Deshpande AJ, et al. AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell. 2014;26:896–908.  https://doi.org/10.1016/j.ccell.2014.10.009.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Yokoyama A, et al. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 2004;24:5639–49.  https://doi.org/10.1128/MCB.24.13.5639-5649.2004.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell. 2007;128:735–45.  https://doi.org/10.1016/j.cell.2007.02.009.CrossRefPubMedGoogle Scholar
  69. 69.
    Kuhn MW, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6:1166–81.  https://doi.org/10.1158/2159-8290.CD-16-0237.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Gu X, et al. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates. J Clin Invest. 2018;128:4260–79.  https://doi.org/10.1172/JCI97117.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Wang A, Han Y, Chen P, Jia N, Minden MD. AACR annual meeting 2018 abstract #2991. Chicago, IL: American Association for Cancer Research; 2018.Google Scholar
  72. 72.
    Luo H, et al. CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia. Blood. 2018;132:837–48.  https://doi.org/10.1182/blood-2017-11-814319.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Huang Y, et al. Identification and characterization of Hoxa9 binding sites in hematopoietic cells. Blood. 2012;119:388–98.  https://doi.org/10.1182/blood-2011-03-341081.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Sun Y, et al. HOXA9 reprograms the enhancer landscape to promote leukemogenesis. Cancer Cell. 2018;34:643–58.  https://doi.org/10.1016/j.ccell.2018.08.018 (e645).CrossRefPubMedGoogle Scholar
  75. 75.
    Ivey A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016.  https://doi.org/10.1056/NEJMoa1507471.CrossRefPubMedGoogle Scholar
  76. 76.
    Shlush LI, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature. 2014;506:328–33.  https://doi.org/10.1038/nature13038.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Krönke J, et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood. 2013;122:100–8.  https://doi.org/10.1182/blood-2013-01-479188.CrossRefPubMedGoogle Scholar
  78. 78.
    Gravina GL, et al. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014;7:85.  https://doi.org/10.1186/s13045-014-0085-1.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Gounder MM, et al. Phase IB study of selinexor, a first-in-class inhibitor of nuclear export, in patients with advanced refractory bone or soft tissue sarcoma. J Clin Oncol. 2016;34:3166–74.  https://doi.org/10.1200/JCO.2016.67.6346.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Abdul Razak AR, et al. First-in-class, first-in-human phase I study of selinexor, a selective inhibitor of nuclear export, in patients with advanced solid tumors. J Clin Oncol. 2016;34:4142–50.  https://doi.org/10.1200/JCO.2015.65.3949.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Chen C, et al. Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia. Blood. 2018;131:855–63.  https://doi.org/10.1182/blood-2017-08-797886.CrossRefPubMedGoogle Scholar
  82. 82.
    Alexander TB, et al. Phase I study of selinexor, a selective inhibitor of nuclear export, in combination with fludarabine and cytarabine, in pediatric relapsed or refractory acute leukemia. J Clin Oncol. 2016;34:4094–101.  https://doi.org/10.1200/JCO.2016.67.5066.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Garzon R, et al. A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. Blood. 2017;129:3165–74.  https://doi.org/10.1182/blood-2016-11-750158.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Etchin J, et al. KPT-8602, a second-generation inhibitor of XPO1-mediated nuclear export, is well tolerated and highly active against AML blasts and leukemia-initiating cells. Leukemia. 2017;31:143–50.  https://doi.org/10.1038/leu.2016.145.CrossRefPubMedGoogle Scholar
  85. 85.
    Hing ZA, et al. Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia. 2016;30:2364–72.  https://doi.org/10.1038/leu.2016.136.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Cancer Genome Atlas Research, N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.  https://doi.org/10.1056/NEJMoa1301689.CrossRefGoogle Scholar
  87. 87.
    Alexandrov LB, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.  https://doi.org/10.1038/nature12477.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Li J, Zhang X, Sejas DP, Bagby GC, Pang Q. Hypoxia-induced nucleophosmin protects cell death through inhibition of p53. J Biol Chem. 2004;279:41275–9.  https://doi.org/10.1074/jbc.C400297200.CrossRefPubMedGoogle Scholar
  89. 89.
    Liu WH, Yung BY. Mortalization of human promyelocytic leukemia HL-60 cells to be more susceptible to sodium butyrate-induced apoptosis and inhibition of telomerase activity by down-regulation of nucleophosmin/B23. Oncogene. 1998;17:3055–64.  https://doi.org/10.1038/sj.onc.1202234.CrossRefPubMedGoogle Scholar
  90. 90.
    Gao H, et al. B23 regulates GADD45a nuclear translocation and contributes to GADD45a-induced cell cycle G2-M arrest. J Biol Chem. 2005;280:10988–96.  https://doi.org/10.1074/jbc.M412720200.CrossRefPubMedGoogle Scholar
  91. 91.
    Okuda M, et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell. 2000;103:127–40.CrossRefPubMedGoogle Scholar
  92. 92.
    Federici L, et al. Nucleophosmin C-terminal leukemia-associated domain interacts with G-rich quadruplex forming DNA. J Biol Chem. 2010;285:37138–49.  https://doi.org/10.1074/jbc.M110.166736.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Arcovito A, et al. Synergic role of nucleophosmin three-helix bundle and a flanking unstructured tail in the interaction with G-quadruplex DNA. J Biol Chem. 2014;289:21230–41.  https://doi.org/10.1074/jbc.M114.565010.CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Scognamiglio PL, et al. G-quadruplex DNA recognition by nucleophosmin: new insights from protein dissection. Biochim Biophys Acta. 2014;1840:2050–9.  https://doi.org/10.1016/j.bbagen.2014.02.017.CrossRefPubMedGoogle Scholar
  95. 95.
    Scott DD, Oeffinger M. Nucleolin and nucleophosmin: nucleolar proteins with multiple functions in DNA repair. Biochem Cell Biol. 2016;94:419–32.  https://doi.org/10.1139/bcb-2016-0068.CrossRefPubMedGoogle Scholar
  96. 96.
    Poletto M, Lirussi L, Wilson DM, 3rd & Tell G. Nucleophosmin modulates stability, activity, and nucleolar accumulation of base excision repair proteins. Mol Biol Cell 25, 1641–52,  https://doi.org/10.1091/mbc.E13-12-0717 (2014).CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Ziv O, et al. Identification of novel DNA-damage tolerance genes reveals regulation of translesion DNA synthesis by nucleophosmin. Nat Commun. 2014;5:5437.  https://doi.org/10.1038/ncomms6437.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Okuwaki M. The structure and functions of NPM1/Nucleophosmin/B23, a multifunctional nucleolar acidic protein. J Biochem. 2008;143:441–8.  https://doi.org/10.1093/jb/mvm222.CrossRefPubMedGoogle Scholar
  99. 99.
    Ahn JY, et al. Nucleophosmin/B23, a nuclear PI(3,4,5)P(3) receptor, mediates the antiapoptotic actions of NGF by inhibiting CAD. Mol Cell. 2005;18:435–45.  https://doi.org/10.1016/j.molcel.2005.04.010.CrossRefPubMedGoogle Scholar
  100. 100.
    Bolli N, et al. A dose-dependent tug of war involving the NPM1 leukaemic mutant, nucleophosmin, and ARF. Leukemia. 2009;23:501–9.  https://doi.org/10.1038/leu.2008.326.CrossRefPubMedGoogle Scholar
  101. 101.
    Dumbar TS, Gentry GA, Olson MO. Interaction of nucleolar phosphoprotein B23 with nucleic acids. Biochemistry. 1989;28:9495–501.CrossRefPubMedGoogle Scholar
  102. 102.
    Sipos K, Olson MO. Nucleolin promotes secondary structure in ribosomal RNA. Biochem Biophys Res Commun. 1991;177:673–8.CrossRefPubMedGoogle Scholar
  103. 103.
    Amin MA, Matsunaga S, Uchiyama S, Fukui K. Depletion of nucleophosmin leads to distortion of nucleolar and nuclear structures in HeLa cells. Biochem J. 2008;415:345–51.  https://doi.org/10.1042/BJ20081411.CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Holmberg Olausson K, Elsir T, Moazemi Goudarzi K, Nister M, Lindstrom MS. NPM1 histone chaperone is upregulated in glioblastoma to promote cell survival and maintain nucleolar shape. Sci Rep. 2015;5:16495.  https://doi.org/10.1038/srep16495.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Lin J, Kato M, Nagata K, Okuwaki M. Efficient DNA binding of NF-kappaB requires the chaperone-like function of NPM1. Nucleic Acids Res. 2017;45:3707–23.  https://doi.org/10.1093/nar/gkw1285.CrossRefPubMedGoogle Scholar
  106. 106.
    Liu CD, et al. The nuclear chaperone nucleophosmin escorts an Epstein-Barr Virus nuclear antigen to establish transcriptional cascades for latent infection in human B cells. PLoS Pathog. 2012;8:e1003084.  https://doi.org/10.1371/journal.ppat.1003084.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Destouches D, et al. Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer. Oncotarget. 2016;7:69397–411.  https://doi.org/10.18632/oncotarget.8043.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Japanese Society of Hematology 2019

Authors and Affiliations

  1. 1.The Stem Cells and Regenerative Medicine CenterBaylor College of MedicineHoustonUSA
  2. 2.Center for Cell and Gene Therapy, Texas Children’s Hospital, Houston Methodist HospitalBaylor College of MedicineHoustonUSA
  3. 3.Centro Ricerca Emato-Oncologica (CREO)Università degli Studi di PerugiaPerugiaItaly
  4. 4.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  5. 5.Department of PediatricsBaylor College of MedicineHoustonUSA

Personalised recommendations