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Research Article

Nucleophosmin 1: from its pathogenic role to a tantalizing therapeutic target in acute myeloid leukemia

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References

  • Falini B, Nicoletti I, Martelli MF, et al. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features. Blood. 2007;109:874–885.
  • Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–2405.
  • Schneider F, Hoster E, Schneider S, et al. Age-dependent frequencies of NPM1 mutations and FLT3-ITD in patients with normal karyotype AML (NK-AML). Ann Hematol. 2012;91:9–18.
  • Zhang M, Yin J, He Q, et al. Chinese and Europeans with acute myeloid leukemia have discordant mutation topographies. Leuk Res. 2018;70:8–12.
  • Martelli MP, Pettirossi V, Thiede C, et al. CD34 + cells from AML with mutated NPM1 harbor cytoplasmic mutated nucleophosmin and generate leukemia in immunocompromised mice. Blood. 2010;116:3907–3922.
  • Rose D, Haferlach T, Schnittger S, et al. Subtype-specific patterns of molecular mutations in acute myeloid leukemia. Leukemia. 2017;31:11–17.
  • La Manna S, Florio D, Di Natale C, et al. Conformational consequences of NPM1 rare mutations: An aggregation perspective in acute myeloid leukemia. Bioorg Chem. 2021;113:104997.
  • Jeon Y, Seo SW, Park S, et al. Identification of two novel NPM1 mutations in patients with acute myeloid leukemia. Ann Lab Med. 2013;33:60–64.
  • Beziat G, Tavitian S, Bertoli S, et al. Dactinomycin in acute myeloid leukemia with NPM1 mutations. Eur J Haematol. 2020;105:302–307.
  • Helbig G, Wozniczka K, Wieclawek A, et al. Clinical relevance of mutant NPM1 and CEBPA in patients with acute myeloid leukemia - preliminary report. Contemp Oncol (Pozn). 2014;18:241–245.
  • Döhner K, Schlenk RF, Habdank M, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. Blood. 2005;106:3740–3746.
  • Juliusson G, Jädersten M, Deneberg S, et al. The prognostic impact of FLT3-ITD and NPM1 mutation in adult AML is age-dependent in the population-based setting. Blood Adv. 2020;4:1094–1101.
  • Cappelli LV, Meggendorfer M, Dicker F, et al. DNMT3A mutations are over-represented in young adults with NPM1 mutated AML and prompt a distinct co-mutational pattern. Leukemia. 2019;33:2741–2746.
  • Yang X, Shi J, Zhang X, et al. Biological and clinical influences of NPM1 in acute myeloid leukemia patients with DNMT3A mutations. Cancer Manag Res. 2018;10:2489–2497. doi:10.2147/CMAR.S166714.
  • Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28:3636–3643.
  • Mitrea DM, Grace CR, Buljan M, et al. Structural polymorphism in the N-terminal oligomerization domain of NPM1. Proc Natl Acad Sci U S A. 2014;111:4466–4471.
  • Grisendi S, Bernardi R, Rossi M, et al. Role of nucleophosmin in embryonic development and tumorigenesis. Nature. 2005;437:147–153.
  • Nachmani D, Bothmer AH, Grisendi S, et al. Germline NPM1 mutations lead to altered rRNA 2'-O-methylation and cause dyskeratosis congenita. Nat Genet. 2019;51(10):1518–1529.
  • Szebeni A, Olson MO. Nucleolar protein B23 has molecular chaperone activities. Protein Sci. 1999;8:905–912.
  • Luchinat E, Chiarella S, Franceschini M, et al. Identification of a novel nucleophosmin-interaction motif in the tumor suppressor p14arf. FEBS J. 2018;285:832–847.
  • Lindström MS. NPM1/B23: a multifunctional chaperone in ribosome biogenesis and Chromatin remodeling. Biochem Res Int. 2011;2011:195209.
  • Cela I, Di Matteo A, Federici L. Nucleophosmin in its interaction with ligands. Int J Mol Sci. 2020;21:4885.
  • Liso A, Castiglione F, Cappuccio A, et al. A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1). Haematologica. 2008;93:1219–1226.
  • Dvorakova D, Racil Z, Borsky M, et al. Clonal heterogeneity in patients with cytogenetically normal acute myeloid leukemia with NPM1 mutations. Leuk Lymphoma. 2013;54:1056–1060.
  • Sportoletti P, Varasano E, Rossi R, et al. The human NPM1 mutation A perturbs megakaryopoiesis in a conditional mouse model. Blood. 2013;121:3447–3458.
  • Martínez-Losada C, Serrano-López J, Serrano-López J, et al. Clonal genetic evolution at relapse of favorable-risk acute myeloid leukemia with NPM1 mutation is associated with phenotypic changes and worse outcomes. Haematologica. 2018;103:e400–e403.
  • Patel JL, Schumacher JA, Frizzell K, et al. Coexisting and cooperating mutations in NPM1-mutated acute myeloid leukemia. Leuk Res. 2017;56:7–12.
  • Loberg MA, Bell RK, Goodwin LO, et al. Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis. Leukemia. 2019;33:1635–1649.
  • Alpermann T, Schnittger S, Eder C, et al. Molecular subtypes of NPM1 mutations have different clinical profiles, specific patterns of accompanying molecular mutations and varying outcomes in intermediate risk acute myeloid leukemia. Haematologica. 2016;101:e55–e58.
  • Falini B, Bolli N, Shan J, 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;107:4514–4523.
  • Chiarella S, De Cola A, Scaglione GL, et al. Nucleophosmin mutations alter its nucleolar localization by impairing G-quadruplex binding at ribosomal DNA. Nucleic Acids Res. 2013;41:3228–3239.
  • Kunchala P, Kuravi S, Jensen R, et al. When the good go bad: mutant NPM1 in acute myeloid leukemia. Blood Rev. 2018;32:167–183.
  • Bailey GD, Doolan L, Baskar A, et al. Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukemia. Sci Rep. 2020;10:17695.
  • Tang Y, Tao Y, Wang L, et al. NPM1 mutant maintains ULK1 protein stability via TRAF6-dependent ubiquitination to promote autophagic cell survival in leukemia. FASEB J. 2021;35:e21192.
  • Wang L, Yang L, Yang Z, et al. Glycolytic enzyme PKM2 mediates autophagic activation to promote cell survival in NPM1-mutated leukemia. Int J Biol Sci. 2019;15:882–894.
  • Di Matteo A, Franceschini M, Paiardini A, et al. Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ. Oncogenesis. 2017;6:e379.
  • Sportoletti P, Celani L, Varasano E, et al. GATA1 epigenetic deregulation contributes to the development of AML with NPM1 and FLT3-ITD cooperating mutations. Leukemia. 2019;33:1827–1832.
  • Wang AJ, Han Y, Jia N, et al. NPM1c impedes CTCF functions through cytoplasmic mislocalization in acute myeloid leukemia. Leukemia. 2020;34:1278–1290.
  • Ando K, Tsushima H, Matsuo E, et al. Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation. J Biol Chem. 2013;288:9457–9467.
  • Johansson H, Simonsson S. Core transcription factors, Oct4, Sox2 and Nanog, individually form complexes with nucleophosmin (Npm1) to control embryonic stem (ES) cell fate determination. Aging (Albany NY). 2010;2:815–822.
  • Brunetti L, Gundry MC, Sorcini D, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018;34:499–512. e9.
  • Mullighan CG, Kennedy A, Zhou X, et al. Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. Leukemia. 2007;21:2000–2009.
  • Zhang W, Zhao C, Zhao J, et al. Inactivation of PBX3 and HOXA9 by down-regulating H3K79 methylation represses NPM1-mutated leukemic cell survival. Theranostics. 2018;8:4359–4371.
  • Wiktorin HG, Nilsson T, Jansson A, et al. Mutated NPM1 in combination with overexpression of Meis1 or Hoxa9 is not sufficient to induce acute myeloid leukemia. Exp Hematol Oncol. 2015;5:25.
  • Ogawara Y, Katsumoto T, Aikawa Y, et al. IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and hypoxia pathways in acute myeloid leukemia. Cancer Res. 2015;75:2005–2016.
  • Dovey OM, Cooper JL, Mupo A, et al. Molecular synergy underlies the co-occurrence patterns and phenotype of NPM1-mutant acute myeloid leukemia. Blood. 2017;130:1911–1922.
  • Havelange V, Ranganathan P, Geyer S, et al. Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. Blood. 2014;123:2412–2415.
  • Papaioannou D, Petri A, Dovey OM, et al. The long non-coding RNA HOXB-AS3 regulates ribosomal RNA transcription in NPM1-mutated acute myeloid leukemia. Nat Commun. 2019;10:5351.
  • Zhu G, Luo H, Feng Y, et al. HOXBLINC long non-coding RNA activation promotes leukemogenesis in NPM1-mutant acute myeloid leukemia. Nat Commun. 2021;12:1956.
  • Tiribelli M, Geromin A, Damiani D, et al. Impact of fludarabine-based induction therapy on outcome of FLT3-/NPM1 + cytogenetically normal acute myeloid leukemia. Am J Hematol. 2012;92:E45–E47.
  • Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–1089.
  • Guièze R, Cornillet-Lefebvre P, Lioure B, et al. Role of autologous hematopoietic stem cell transplantation according to the NPM1/FLT3-ITD molecular status for cytogenetically normal AML patients: a GOELAMS study. Am J Hematol. 2012;87:1052–1056.
  • Huang Y, Hu J, Lu T, et al. Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis. Cancer Manag Res. 2019;11:4129–4142.
  • Röllig C, Bornhäuser M, Kramer M, et al. Allogeneic stem-cell transplantation in patients with NPM1-mutated acute myeloid leukemia: results from a prospective donor versus no-donor analysis of patients after upfront HLA typing within the SAL-AML 2003 trial. J Clin Oncol. 2015;33:403–410.
  • Gorin NC, Labopin M, Meloni G, et al. Impact of FLT3 ITD/NPM1 mutation status in adult patients with acute myelocytic leukemia autografted in first remission. Haematologica. 2013;98:e12–e14.
  • Boddu P, Kantarjian H, Borthakur G, et al. Co-occurrence of FLT3-TKD and NPM1 mutations defines a highly favorable prognostic AML group. Blood Adv. 2017;1:1546–1550.
  • Prata PH, Bally C, Prebet T, et al. NPM1 mutation is not associated with prolonged complete remission in acute myeloid leukemia patients treated with hypomethylating agents. Haematologica. 2018;103:e455–e457.
  • Wei A, Tan P, Perruzza S, et al. Maintenance lenalidomide in combination with 5-azacitidine as post-remission therapy for acute myeloid leukemia. Br J Haematol. 2015;169:199–210.
  • Perriello VM, Gionfriddo I, Rossi R, et al. CD123 is consistently expressed on NPM1-mutated AML cells. Cancers (Basel). 2021;13:496.
  • Qin FX, Shao HY, Chen XC, et al. Knockdown of NPM1 by RNA interference inhibits cells proliferation and induces apoptosis in leukemic cell line. Int J Med Sci. 2011;8:287–294.
  • Andresen V, Erikstein BS, Mukherjee H, et al. Anti-proliferative activity of the NPM1 interacting natural product avrainvillamide in acute myeloid leukemia. Cell Death Dis. 2016;7:e2497.
  • Nabbouh AI, Hleihel RS, Saliba JL, et al. Imidazoquinoxaline derivative EAPB0503: A promising drug targeting mutant nucleophosmin 1 in acute myeloid leukemia. Cancer. 2017;123:1662–1673.
  • Yang K, Wang M, Zhao Y, et al. A redox mechanism underlying nucleolar stress sensing by nucleophosmin. Nat Commun. 2016;7:13599.
  • Gionfriddo I, Brunetti L, Mezzasoma F, et al. Dactinomycin induces complete remission associated with nucleolar stress response in relapsed/refractory NPM1-mutated AML. Leukemia. 2021;35:2552–2562.
  • Šašinková M, Heřman P, Holoubek A, et al. NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization. Sci Rep. 2021;11:1084.
  • Penthala NR, Ketkar A, Sekhar KR, et al. 1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: anti-cancer agents that target nucleophosmin 1 (NPM1). Bioorg Med Chem. 2015;23:7226–7233.
  • Traver G, Sekhar KR, Crooks PA, et al. Targeting NPM1 in irradiated cells inhibits NPM1 binding to RAD51, RAD51 foci formation and radiosensitizes NSCLC. Cancer Lett. 2021;500:220–227.
  • De Cola A, Franceschini M, Di Matteo A, et al. N6l pseudopeptide interferes with nucleophosmin protein-protein interactions and sensitizes leukemic cells to chemotherapy. Cancer Lett. 2018;412:272–282.
  • Martelli MP, Gionfriddo I, Mezzasoma F, et al. Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. Blood. 2015;125:3455–3465.
  • Nazha A, Bueso-Ramos C, Estey E, et al. The addition of All-trans retinoic acid to chemotherapy may not improve the outcome of patient with NPM1 mutated acute myeloid leukemia. Front Oncol. 2013;3:218.
  • Chi HT, Ly BT, Vu HA, et al. Down-regulated expression of NPM1 in IMS-M2 cell line by (-)-epigallocatechin-3-gallate. Asian Pac J Trop Biomed. 2014;4:570–574.
  • Yi S, Wen L, He J, et al. Deguelin, a selective silencer of the NPM1 mutant, potentiates apoptosis and induces differentiation in AML cells carrying the NPM1 mutation. Ann Hematol. 2015;94:201–210.
  • Zhang X, Zhao Z, Yi S, et al. Deguelin induced differentiation of mutated NPM1 acute myeloid leukemia in vivo and in vitro. Anticancer Drugs. 2017;28:723–738.
  • Forghieri F, Riva G, Lagreca I, et al. Characterization and dynamics of specific T cells against nucleophosmin-1 (NPM1)-mutated peptides in patients with NPM1-mutated acute myeloid leukemia. Oncotarget. 2019;10:869–882.
  • Greiner J, Schneider V, Schmitt M, et al. Immune responses against the mutated region of cytoplasmatic NPM1 might contribute to the favorable clinical outcome of AML patients with NPM1 mutations (NPM1mut). Blood. 2013;122:1087–1088.
  • Casalegno-Garduño R, Meier C, Schmitt A, et al. Immune responses to RHAMM in patients with acute myeloid leukemia after chemotherapy and allogeneic stem cell transplantation. Clin Dev Immunol. 2012;2012:146463.
  • De Propris MS, Raponi S, Diverio D, et al. High CD33 expression levels in acute myeloid leukemia cells carrying the nucleophosmin (NPM1) mutation. Haematologica. 2011;96:1548–1551.
  • Schlenk RF, Paschka P, Krzykalla J, et al. Gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia: early results from the prospective randomized AMLSG 09-09 phase III study. J Clin Oncol. 2020;38:623–632.
  • Kapp-Schwoerer S, Weber D, Corbacioglu A, et al. Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial. Blood. 2020;136:3041–3050.
  • Klossowski S, Miao H, Kempinska K, et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J Clin Invest. 2020;130:981–997.
  • Kühn MW, Song E, Feng Z, et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Discov. 2016;6:1166–1181.
  • Carter BZ, Tao W, Mak PY, et al. Menin inhibition decreases Bcl-2 and synergizes with venetoclax in NPM1/FLT3-mutated AML. Blood. 2021;138:1637–1641.
  • Uckelmann HJ, Kim SM, Wong EM, et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science. 2020;367:586–590.
  • Pemmaraju N, Konopleva M. Approval of tagraxofusp-erzs for blastic plasmacytoid dendritic cell neoplasm. Blood Adv. 2020;4:4020–4027.
  • Testa U, Pelosi E, Castelli G. CD123 as a therapeutic target in the treatment of hematological malignancies. Cancers (Basel). 2020;11:1358.
  • Zhang S, Qin F, Yang L, et al. Nucleophosmin mutations induce chemosensitivity in THP-1 leukemia cells by suppressing NF-κB activity and regulating Bax/Bcl-2 expression. J Cancer. 2016;7:2270–2279.
  • DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135:791–803.
  • Tiong IS, Dillon R, Ivey A, et al. Venetoclax induces rapid elimination of NPM1 mutant measurable residual disease in combination with low-intensity chemotherapy in acute myeloid leukemia. Br J Haematol. 2021;192:1026–1030.
  • Cho H, Jang JE, Eom JI, et al. Arsenic trioxide synergistically promotes the antileukaemic activity of venetoclax by downregulating Mcl-1 in acute myeloid leukemia cells. Exp Hematol Oncol. 2021;10:28.
  • DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629.
  • Lachowiez CA, Loghavi S, Kadia TM, et al. Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens. Blood Adv. 2020;4(7):1311–1320.
  • Prokoph N, Probst NA, Lee LC, et al. IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma. Blood. 2020;136:1657–1669.
  • Kuravi S, Cheng J, Fangman G, et al. Preclinical evaluation of Gilteritinib on NPM1-ALK-driven anaplastic large cell lymphoma cells. Mol Cancer Res. 2021;19:913–920.
  • Huang M, Garcia JS, Thomas D, et al. Autophagy mediates proteolysis of NPM1 and HEXIM1 and sensitivity to BET inhibition in AML cells. Oncotarget. 2016;7:74917–74930.
  • Mason EF, Kuo FC, Hasserjian RP, et al. A distinct immunophenotype identifies a subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. Am J Hematol. 2018;93:504–510.
  • Patel SS, Pinkus GS, Ritterhouse LL, et al. High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia. Am J Hematol. 2019;94(8):921–928.
  • Krönke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: A study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29:2709–2716.
  • Heiblig M, Duployez N, Marceau A, et al. The impact of DNMT3A status on NPM1 MRD predictive value and survival in elderly AML patients treated intensively. Cancers (Basel). 2021;13(9):2156.
  • Hubmann M, Köhnke T, Hoster E, et al. Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse. Haematologica. 2014;99(8):1317–1325.
  • Balsat M, Renneville A, Thomas X, et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the acute leukemia French Association Group. J Clin Oncol. 2017;35(2):185–193.
  • Tiong IS, Dillon R, Ivey A, et al. Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia. Blood Adv. 2021;5(23):5107–5111.
  • Cornelissen JJ, Versluis J, Passweg JR, et al. Comparative therapeutic value of post- remission approaches in patients with acute myeloid leukemia aged 40-60 years. Leukemia. 2015;29:1041–1050.
  • Karas M, Steinerova K, Lysak D, et al. Pre-transplant quantitative determination of NPM1 mutation significantly predicts outcome of aIlogeneic hematopoietic stem cell transplantation in patients with normal karyotype AML in complete remission. Anticancer Res. 2016;36(10):5487–5498.
  • Delsing Malmberg E, Johansson Alm S, Nicklasson M, et al. Minimal residual disease assessed with deep sequencing of NPM1 mutations predicts relapse after allogeneic stem cell transplant in AML. Leuk Lymphoma. 2019;60(2):409–417.
  • Dillon R, Hills RK, Freeman SD, et al. Molecular MRD status and outcome after transplantation in NPM1 mutated AML: results from the UK NCRI AML17 study. Blood. 2020;135(9):680–688.
  • Platzbecker U, Middeke JM, Sockel K, et al. Minimal-residual disease guided treatment with azacitidine in MDS/AML patients at imminent risk of relapse: results of the prospective RELAZA2 trial. Blood. 2017;130:565.
  • Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal measurable residual disease in AML: A consensus document from the European LeukemiaNet MRD working party. Blood. 2018;131:1275–1291.
  • Pettersson L, Johansson Alm S, Almstedt A, et al. Comparison of RNA- and DNA-based methods for measurable residual disease analysis in NPM1-mutated acute myeloid leukemia. Int J Lab Hematol. 2021;43(4):664–674.
  • Du Pisani LA, Shires K. Development of a flow cytometric method to detect the presence of mutated nucleophosmin 1 in acute myeloid leukemia. Hematol Oncol Stem Cell Ther. 2015;8(3):106–114.
  • Chopra A, Soni S, Pati H, et al. Nucleophosmin mutation analysis in acute myeloid leukemia: immunohistochemistry as a surrogate for molecular techniques. Indian J Med Res. 2016;143(6):763–768.
  • Höllein A, Meggendorfer M, Dicker F, et al. NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse. Blood Adv. 2018;2(22):3118–3125.