The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms
Abstract
:1. Introduction
2. NPM1 Protein in the Normal Cell
3. NPM1 in Human Cancer
3.1. Acute Myeloid Leukemia (AML) with Mutated NPM1; A Myeloid Neoplasm with Unique Features
3.2. Prognosis of NPM1-Mutated AML
4. Minimal Residual Disease (MRD) Monitoring in NPM1-Mutated AML
5. NPM1 Mutations in Myeloid Neoplasms with <20% Blasts
6. Summary
Funding
Conflicts of Interest
References
- Kang, Y.J.; Olson, M.O.; Busch, H. Phosphorylation of acid-soluble proteins in isolated nucleoli of Novikoff hepatoma ascites cells. Effects of divalent cations. J. Biol. Chem. 1974, 249, 5580–5585. [Google Scholar] [CrossRef]
- Kang, Y.J.; Olson, M.O.; Jones, C.; Busch, H. Nucleolar phosphoproteins of normal rat liver and Novikoff hepatoma ascites cells. Cancer Res. 1975, 35, 1470–1475. [Google Scholar] [PubMed]
- Chan, W.Y.; Liu, Q.R.; Borjigin, J.; Busch, H.; Rennert, O.M.; Tease, L.A.; Chan, P.K. Characterization of the Cdna-Encoding Human Nucleophosmin and Studies of Its Role in Normal and Abnormal Growth. Biochemistry 1989, 28, 1033–1039. [Google Scholar] [CrossRef] [PubMed]
- Grisendi, S.; Bernardi, R.; Rossi, M.; Cheng, K.; Khandker, L.; Manova, K.; Pandolfi, P.P. Role of nucleophosmin in embryonic development and tumorigenesis. Nature 2005, 437, 147–153. [Google Scholar] [CrossRef] [PubMed]
- Falini, B.; Mecucci, C.; Tiacci, E.; Alcalay, M.; Rosati, R.; Pasqualucci, L.; La Starza, R.; Diverio, D.; Colombo, E.; Santucci, A.; et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N. Engl. J. Med. 2005, 352, 254–266. [Google Scholar] [CrossRef]
- Borer, R.A.; Lehner, C.F.; Eppenberger, H.M.; Nigg, E.A. Major nucleolar proteins shuttle between nucleus and cytoplasm. Cell 1989, 56, 379–390. [Google Scholar] [CrossRef]
- Yun, J.P.; Chew, E.C.; Liew, C.T.; Chan, J.Y.; Jin, M.L.; Ding, M.X.; Fai, Y.H.; Li, H.K.; Liang, X.M.; Wu, Q.L. Nucleophosmin/B23 is a proliferate shuttle protein associated with nuclear matrix. J. Cell Biochem. 2003, 90, 1140–1148. [Google Scholar] [CrossRef] [PubMed]
- Hingorani, K.; Szebeni, A.; Olson, M.O. Mapping the functional domains of nucleolar protein B23. J. Biol. Chem. 2000, 275, 24451–24457. [Google Scholar] [CrossRef] [Green Version]
- Szebeni, A.; Olson, M.O. Nucleolar protein B23 has molecular chaperone activities. Protein Sci. 1999, 8, 905–912. [Google Scholar] [CrossRef] [Green Version]
- Okuwaki, M.; Tsujimoto, M.; Nagata, K. The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-dependent kinase and by association with its subtype. Mol. Biol. Cell 2002, 13, 2016–2030. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Okuwaki, M.; Matsumoto, K.; Tsujimoto, M.; Nagata, K. Function of nucleophosmin/B23, a nucleolar acidic protein, as a histone chaperone. FEBS Lett. 2001, 506, 272–276. [Google Scholar] [CrossRef] [Green Version]
- Swaminathan, V.; Kishore, A.H.; Febitha, K.K.; Kundu, T.K. Human histone chaperone nucleophosmin enhances acetylation-dependent chromatin transcription. Mol. Cell. Biol. 2005, 25, 7534–7545. [Google Scholar] [CrossRef] [Green Version]
- Falini, B.; Nicoletti, I.; Martelli, M.F.; Mecucci, C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc(+) AML): Biologic and clinical features. Blood 2007, 109, 874–885. [Google Scholar] [CrossRef] [Green Version]
- Falini, B.; Bolli, N.; Liso, A.; Martelli, M.P.; Mannucci, R.; Pileri, S.; Nicoletti, I. Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: Molecular basis and clinical implications. Leukemia 2009, 23, 1731–1743. [Google Scholar] [CrossRef] [PubMed]
- Wang, D.; Baumann, A.; Szebeni, A.; Olson, M.O. The nucleic acid binding activity of nucleolar protein B23.1 resides in its carboxyl-terminal end. J. Biol. Chem. 1994, 269, 30994–30998. [Google Scholar] [CrossRef]
- Savkur, R.S.; Olson, M.O. Preferential cleavage in pre-ribosomal RNA byprotein B23 endoribonuclease. Nucleic Acids Res. 1998, 26, 4508–4515. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chang, J.H.; Olson, M.O. Structure of the gene for rat nucleolar protein B23. J. Biol. Chem. 1990, 265, 18227–18233. [Google Scholar] [CrossRef]
- Wang, D.; Umekawa, H.; Olson, M.O. Expression and subcellular locations of two forms of nucleolar protein B23 in rat tissues and cells. Cell Mol. Biol. Res. 1993, 39, 33–42. [Google Scholar]
- Herrera, J.E.; Correia, J.J.; Jones, A.E.; Olson, M.O. Sedimentation analyses of the salt- and divalent metal ion-induced oligomerization of nucleolar protein B23. Biochemistry 1996, 35, 2668–2673. [Google Scholar] [CrossRef]
- Namboodiri, V.M.; Akey, I.V.; Schmmmidt-Zachmann, M.S.; Head, J.F.; Akey, C.W. The structure and function of Xenopus NO38-core, a histone chaperone in the nucleolus. Structure 2004, 12, 2149–2160. [Google Scholar] [CrossRef] [Green Version]
- Tanaka, M.; Sasaki, H.; Kino, I.; Sugimura, T.; Terada, M. Genes preferentially expressed in embryo stomach are predominantly expressed in gastric cancer. Cancer Res. 1992, 52, 3372–3377. [Google Scholar]
- Nozawa, Y.; Van Belzen, N.; Van der Made, A.C.; Dinjens, W.N.; Bosman, F.T. Expression of nucleophosmin/B23 in normal and neoplastic colorectal mucosa. J. Pathol. 1996, 178, 48–52. [Google Scholar] [CrossRef]
- Shields, L.B.; Gercel-Taylor, C.; Yashar, C.M.; Wan, T.C.; Katsanis, W.A.; Spinnato, J.A.; Taylor, D.D. Induction of immune responses to ovarian tumor antigens by multiparity. J. Soc. Gynecol. Investig. 1997, 4, 298–304. [Google Scholar] [CrossRef]
- Subong, E.N.; Shue, M.J.; Epstein, J.I.; Briggman, J.V.; Chan, P.K.; Partin, A.W. Monoclonal antibody to prostate cancer nuclear matrix protein (PRO:4-216) recognizes nucleophosmin/B23. Prostate 1999, 39, 298–304. [Google Scholar] [CrossRef]
- Tsui, K.H.; Cheng, A.J.; Chang, P.; Pan, T.L.; Yung, B.Y. Association of nucleophosmin/B23 mRNA expression with clinical outcome in patients with bladder carcinoma. Urology 2004, 64, 839–844. [Google Scholar] [CrossRef]
- Redner, R.L.; Rush, E.A.; Faas, S.; Rudert, W.A.; Corey, S.J. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996, 87, 882–886. [Google Scholar] [CrossRef] [Green Version]
- Morris, S.W.; Kirstein, M.N.; Valentine, M.B.; Dittmer, K.G.; Shapiro, D.N.; Saltman, D.L.; Look, A.T. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 1994, 263, 1281–1284. [Google Scholar] [CrossRef] [PubMed]
- Raimondi, S.C.; Dube, I.D.; Valentine, M.B.; Mirro, J.; Jr Watt, H.J.; Larson, R.A.; Bitter, M.A.; Le Beau, M.M.; Rowley, J.D. Clinicopathologic manifestations and breakpoints of the t(3;5) in patients with acute nonlymphocytic leukemia. Leukemia 1989, 3, 42–47. [Google Scholar]
- Yoneda-Kato, N.; Look, A.T.; Kirstein, M.N.; Valentine, M.B.; Raimondi, S.C.; Cohen, K.J.; Carroll, A.J.; Morris, S.W. The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene 1996, 12, 265–275. [Google Scholar]
- Dergunova, N.; Bulycheva, T.I.; Artemenko, E.G.; Shpakova, A.P.; Pegova, A.N.; Gemjian, E.G.; Dudnik, O.A.; Zatsepina, O.V.; Malashenko, O.S. A major nucleolar protein B23 as a marker of proliferation activity of human peripheral lymphocytes. Immunol. Lett. 2002, 83, 67–72. [Google Scholar] [CrossRef]
- Zeller, K.I.; Haggerty, T.J.; Barrett, J.F.; Guo, Q.; Wonsey, D.R.; Dang, C.V. Characterization of nucleophosmin (B23) as a Myc target by scanning chromatin immunoprecipitation. J. Biol. Chem. 2001, 276, 48285–48291. [Google Scholar] [CrossRef] [Green Version]
- Boon, K.; Caron, H.N.; van Asperen, R.; Valentijn, L.; Hermus, M.C.; van Sluis, P.; Roobeek, I.; Weis, I.; Voute, P.A.; Schwab, M.; et al. N-myc enhances the expression of a large set of genes functioning in ribosome biogenesis and protein synthesis. EMBO J. 2001, 20, 1383–1393. [Google Scholar] [CrossRef]
- Takemura, M.; Sato, K.; Nishio, M.; Akiyama, T.; Umekawa, H.; Yoshida, S. Nucleolar protein B23.1 binds to retinoblastoma protein and synergistically stimulates DNA polymerase alpha activity. J. Biochem. 1999, 125, 904–909. [Google Scholar] [CrossRef]
- Dumbar, T.S.; Gentry, G.A.; Olson, M.O. Interaction of nucleolar phosphoprotein B23 with nucleic acids. Biochemistry 1989, 28, 9495–9501. [Google Scholar] [CrossRef]
- Prestayko, A.W.; Klomp, G.R.; Schmoll, D.J.; Busch, H. Comparison of proteins of ribosomal subunits and nucleolar preribosomal particles from Novikoff hepatoma ascites cells by two-dimensional polyacrylamide gel electrophoresis. Biochemistry 1974, 13, 1945–1951. [Google Scholar] [CrossRef] [PubMed]
- Olson, M.O.; Wallace, M.O.; Herrera, A.H.; Marshall-Carlson, L.; Hunt, R.C. Preribosomal ribonucleoprotein particles are a major component of a nucleolar matrix fraction. Biochemistry 1986, 25, 484–491. [Google Scholar] [CrossRef] [PubMed]
- Kondo, T.; Minamino, N.; Nagamura-Inoue, T.; Matsumoto, M.; Taniguchi, T.; Tanaka, N. Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity. Oncogene 1997, 15, 1275–1281. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bertwistle, D.; Sugimoto, M.; Sherr, C.J. Physical and functional interactions of the Arf tumor suppressor protein with nucleophosmin/B23. Mol. Cell. Biol. 2004, 24, 985–996. [Google Scholar] [CrossRef] [Green Version]
- Kuo, M.L.; den Besten, W.; Bertwistle, D.; Roussel, M.F.; Sherr, C.J. N-terminal polyubiquitination and degradation of the Arf tumor suppressor. Genes Dev. 2004, 18, 1862–1874. [Google Scholar] [CrossRef] [Green Version]
- Brady, S.N.; Yu, Y.; Maggi, L.B.; Weber, J.D. ARF impedes NPM/B23 shuttling in an Mdm2-sensitive tumor suppressor pathway. Mol. Cell. Biol. 2004, 24, 9327–9338. [Google Scholar] [CrossRef] [Green Version]
- Kurki, S.; Peltonen, K.; Latonen, L.; Kiviharju, T.M.; Ojala, P.M.; Meek, D.; Laiho, M. Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 2004, 5, 465–475. [Google Scholar] [CrossRef] [Green Version]
- Oren, M. Regulation of the p53 tumor suppressor protein. J. Biol. Chem. 1999, 274, 36031–36034. [Google Scholar] [CrossRef] [Green Version]
- Gao, H.; Jin, S.Q.; Song, Y.M.; Fu, M.; Wang, M.R.; Liu, Z.H.; Wu, M.; Zhan, Q.M. B23 regulates GADD45a nuclear translocation and contributes to GADD45a-induced cell cycle G(2)-M arrest. J. Biol. Chem. 2005, 280, 10988–10996. [Google Scholar] [CrossRef] [Green Version]
- Wu, M.H.; Chang, J.H.; Yung, B.Y. Resistance to UV-induced cell-killing in nucleophosmin/B23 over-expressed NIH 3T3 fibroblasts: Enhancement of DNA repair and up-regulation of PCNA in association with nucleophosmin/B23 over-expression. Carcinogenesis 2002, 23, 93–100. [Google Scholar] [CrossRef] [Green Version]
- Okuda, M.; Horn, H.F.; Tarapore, P.; Tokuyama, Y.; Smulian, A.G.; Chan, P.K.; Knudsen, E.S.; Hofmann, I.A.; Snyder, J.D.; Bove, K.E.; et al. Nucleophosmin/B23 is a target of CDK2/cyclin E in centrosome duplication. Cell 2000, 103, 127–140. [Google Scholar] [CrossRef] [Green Version]
- Falini, B.; Brunetti, L.; Sportoletti, P.; Martelli, M.P. NPM1-mutated acute myeloid leukemia: From bench to bedside. Blood 2020, 136, 1707–1721. [Google Scholar] [CrossRef]
- Grimwade, D.; Ivey, A.; Huntly, B.J.P. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood 2016, 127, 29–41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Arber, D.A.; Brunning, R.D.; Le Beau, M.M.; Falini, B.; Vardiman, J.W.; Porwit, A.; Thiele, J.; Foucar, K.; Dohner, H.; Bloomfield, C.D. Acute myeloid leukaemia with recurrent genetic abnormalities. In WHO CLassification of Tumours of Haematopoietic and Lymphoid Tissue; Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., Arber, D.A., Hasserjian, R.P., Le Beau, M.M., et al., Eds.; International Agency for Research on Cancer: Lyon, France, 2017; pp. 141–142. [Google Scholar]
- Verhaak, R.G.W.; Goudswaard, C.S.; van Putten, W.; Bijl, M.A.; Sanders, M.A.; Hugens, W.; Uitterlinden, A.G.; Erpelinck, C.A.J.; Delwel, R.; Lowenberg, B.; 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, 3747–3754. [Google Scholar] [CrossRef] [PubMed]
- Nakagawa, M.; Kameoka, Y.; Suzuki, R. Nucleophosmin in acute myelogenous leukemia. N. Engl. J. Med. 2005, 352, 1819–1820. [Google Scholar]
- Falini, B.; Bolli, N.; Shan, J.; Martelli, M.P.; Liso, A.; Pucciarini, A.; Bigerna, B.; Pasqualucci, L.; Mannucci, R.; Rosati, R.; 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. [Google Scholar] [CrossRef] [PubMed]
- Grisendi, S.; Pandolfi, P.P. NPM mutations in acute myelogenous leukemia. N. Engl. J. Med. 2005, 352, 291–292. [Google Scholar] [CrossRef]
- Schnittger, S.; Schoch, C.; Kern, W.; Mecucci, C.; Tschulik, C.; Martelli, M.F.; Haferlach, T.; Hiddemann, W.; Falini, B. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005, 106, 3733–3739. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dohner, K.; Schlenk, R.F.; Habdank, M.; Scholl, C.; Rucker, F.G.; Corbacioglu, A.; Bullinger, L.; Frohling, S.; Dohner, H. 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. [Google Scholar] [CrossRef] [Green Version]
- Diaz-Beya, M.; Rozman, M.; Pratcorona, M.; Torrebadell, M.; Camos, M.; Aguilar, J.L.; Esteve, J. The prognostic value of multilineage dysplasia in de novo acute myeloid leukemia patients with intermediate-risk cytogenetics is dependent on NPM1 mutational status. Blood 2010, 116, 6147–6148. [Google Scholar] [CrossRef] [PubMed]
- Falini, B.; Macijewski, K.; Weiss, T. Multilineage dysplasia has no impact on biologic, clinicopathologic, and prognostic features of AML with mutated nucleophosmin (NPM1) (vol 115, pg 3776, 2010). Blood 2010, 116, 1017. [Google Scholar]
- Falini, B.; Martelli, M.P.; Bolli, N.; Sportoletti, P.; Liso, A.; Tiacci, E.; Haferlach, T. Acute myeloid leukemia with mutated nucleophosmin (NPM1): Is it a distinct entity? Blood 2011, 117, 1109–1120. [Google Scholar] [CrossRef] [PubMed]
- Hollein, A.; Meggendorfer, M.; Dicker, F.; Jeromin, S.; Nadarajah, N.; Kern, W.; Haferlach, C.; Haferlach, T. NPM1 mutated AML can relapse with wild-type NPM1: Persistent clonal hematopoiesis can drive relapse. Blood Adv. 2018, 2, 3118–3125. [Google Scholar] [CrossRef]
- Forghieri, F.; Comoli, P.; Marasca, R.; Potenza, L.; Luppi, M. Minimal/Measurable Residual Disease Monitoring in NPM1-Mutated Acute Myeloid Leukemia: A Clinical Viewpoint and Perspectives. Int. J. Mol. Sci. 2018, 19, 3492. [Google Scholar] [CrossRef] [Green Version]
- Brown, P.; McIntyre, E.; Rau, R.; Meshinchi, S.; Lacayo, N.; Dahl, G.; Alonzo, T.A.; Chang, M.; Arceci, R.J.; Small, D. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 2007, 110, 979–985. [Google Scholar] [CrossRef] [Green Version]
- Schlenk, R.F.; Dohner, K.; Krauter, J.; Frohling, S.; Corbacioglu, A.; Bullinger, L.; Habdank, M.; Spath, D.; Morgan, M.; Benner, A.; et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 2008, 358, 1909–1918. [Google Scholar] [CrossRef] [Green Version]
- Thiede, C.; Koch, S.; Creutzig, E.; Steudel, C.; Illmer, T.; Schaich, M.; Ehninger, G. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood 2006, 107, 4011–4020. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Haferlach, C.; Mecucci, C.; Schnittger, S.; Kohlmann, A.; Mancini, M.; Cuneo, A.; Testoni, N.; Rege-Cambrin, G.; Santucci, A.; Vignetti, M.; et al. AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features. Blood 2009, 114, 3024–3032. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Micol, J.B.; Boissel, N.; Renneville, A.; Castaigne, S.; Gardin, C.; Preudhomme, C.; Dombret, H. The role of cytogenetic abnormalities in acute myeloid leukemia with NPM1 mutations and no FLT3 internal tandem duplication. Blood 2009, 114, 4601–4602. [Google Scholar] [CrossRef] [PubMed]
- Gale, R.E.; Green, C.; Allen, C.; Mead, A.J.; Burnett, A.K.; Hills, R.K.; Linch, D.C. Medical Research Council Adult Leukaemia Working P: The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008, 111, 2776–2784. [Google Scholar] [CrossRef] [Green Version]
- Pratcorona, M.; Brunet, S.; Nomdedeu, J.; Ribera, J.M.; Tormo, M.; Duarte, R.; Escoda, L.; Guardia, R.; Queipo de Llano, M.P.; Salamero, O.; et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: Relevance to post-remission therapy. Blood 2013, 121, 2734–2738. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Schlenk, R.F.; Kayser, S.; Bullinger, L.; Kobbe, G.; Casper, J.; Ringhoffer, M.; Held, G.; Brossart, P.; Lubbert, M.; Salih, H.R.; et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood 2014, 124, 3441–3449. [Google Scholar] [CrossRef] [Green Version]
- Becker, H.; Marcucci, G.; Maharry, K.; Radmacher, M.D.; Mrozek, K.; Margeson, D.; Whitman, S.P.; Wu, Y.Z.; Schwind, S.; Paschka, P.; et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: A Cancer and Leukemia Group B study. J. Clin. Oncol. 2010, 28, 596–604. [Google Scholar] [CrossRef] [Green Version]
- Loghavi, S.; Zuo, Z.; Ravandi, F.; Kantarjian, H.M.; Bueso-Ramos, C.; Zhang, L.; Singh, R.R.; Patel, K.P.; Medeiros, L.J.; Stingo, F.; et al. Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations. J. Hematol. Oncol. 2014, 7, 74. [Google Scholar] [CrossRef] [Green Version]
- Ossenkoppele, G.; Schuurhuis, G.J. MRD in AML: Does it already guide therapy decision-making? Hematol. Am. Soc. Hematol Educ. Program 2016, 2016, 356–365. [Google Scholar] [CrossRef] [PubMed]
- Gorello, P.; Cazzaniga, G.; Alberti, F.; Dell’Oro, M.G.; Gottardi, E.; Specchia, G.; Roti, G.; Rosati, R.; Martelli, M.F.; Diverio, D.; et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 2006, 20, 1103–1108. [Google Scholar] [CrossRef] [Green Version]
- Papadaki, C.; Dufour, A.; Seibl, M.; Schneider, S.; Bohlander, S.K.; Zellmeier, E.; Mellert, G.; Hiddemann, W.; Spiekermann, K. Monitoring minimal residual disease in acute myeloid leukaemia with NPM1 mutations by quantitative PCR: Clonal evolution is a limiting factor. Br. J. Haematol. 2009, 144, 517–523. [Google Scholar] [CrossRef]
- Schnittger, S.; Kern, W.; Tschulik, C.; Weiss, T.; Dicker, F.; Falini, B.; Haferlach, C.; Haferlach, T. Minimal residual disease levels assessed by NPM1 mutation-specific RQ-PCR provide important prognostic information in AML. Blood 2009, 114, 2220–2231. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hubmann, M.; Kohnke, T.; Hoster, E.; Schneider, S.; Dufour, A.; Zellmeier, E.; Fiegl, M.; Braess, J.; Bohlander, S.K.; Subklewe, M.; 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, 1317–1325. [Google Scholar] [CrossRef] [PubMed]
- Alizad Ghandforoush, N.; Chahardouli, B.; Rostami, S.; Ghadimi, H.; Ghasemi, A.; Alimoghaddam, K.; Ghavamzadeh, A.; Nadali, F. Evaluation of Minimal Residual Disease in Acute Myeloid Leukemia with NPM1 Marker. Int. J. Hematol. Oncol. Stem. Cell Res. 2016, 10, 147–152. [Google Scholar]
- Balsat, M.; Renneville, A.; Thomas, X.; de Botton, S.; Caillot, D.; Marceau, A.; Lemasle, E.; Marolleau, J.P.; Nibourel, O.; Berthon, C.; 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, 185–193. [Google Scholar] [CrossRef]
- Patkar, N.; Kodgule, R.; Kakirde, C.; Raval, G.; Bhanshe, P.; Joshi, S.; Chaudhary, S.; Badrinath, Y.; Ghoghale, S.; Kadechkar, S.; et al. Clinical impact of measurable residual disease monitoring by ultradeep next generation sequencing in NPM1 mutated acute myeloid leukemia. Oncotarget 2018, 9, 36613–36624. [Google Scholar] [CrossRef]
- Schuurhuis, G.J.; Heuser, M.; Freeman, S.; Bene, M.C.; Buccisano, F.; Cloos, J.; Grimwade, D.; Haferlach, T.; Hills, R.K.; Hourigan, C.S.; et al. Minimal/measurable residual disease in AML: A consensus document from the European LeukemiaNet MRD Working Party. Blood 2018, 131, 1275–1291. [Google Scholar] [CrossRef] [Green Version]
- Shayegi, N.; Kramer, M.; Bornhauser, M.; Schaich, M.; Schetelig, J.; Platzbecker, U.; Rollig, C.; Heiderich, C.; Landt, O.; Ehninger, G.; et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood 2013, 122, 83–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hantel, A.; Stock, W.; Kosuri, S. Molecular Minimal Residual Disease Testing in Acute Myeloid Leukemia: A Review for the Practicing Clinician. Clin. Lymphoma Myeloma Leuk 2018, 18, 636–647. [Google Scholar] [CrossRef]
- Dohner, H.; Estey, E.; Grimwade, D.; Amadori, S.; Appelbaum, F.R.; Buchner, T.; Dombret, H.; Ebert, B.L.; Fenaux, P.; Larson, R.A.; et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017, 129, 424–447. [Google Scholar] [CrossRef] [Green Version]
- Gu, X.; Ebrahem, Q.; Mahfouz, R.Z.; Hasipek, M.; Enane, F.; Radivoyevitch, T.; Rapin, N.; Przychodzen, B.; Hu, Z.; Balusu, R.; et al. Leukemogenic nucleophosmin mutation disrupts the transcription factor hub that regulates granulomonocytic fates. J. Clin. Investig. 2018, 128, 4260–4279. [Google Scholar] [CrossRef] [Green Version]
- Patel, S.S.; Kuo, F.C.; Gibson, C.J.; Steensma, D.P.; Soiffer, R.J.; Alyea, E.P.; 3rd Chen, Y.A.; Fathi, A.T.; Graubert, T.A.; Brunner, A.M.; et al. High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML. Blood 2018, 131, 2816–2825. [Google Scholar] [CrossRef] [Green Version]
- Tomlinson, B.; Lazarus, H.M. Enhancing acute myeloid leukemia therapy—Monitoring response using residual disease testing as a guide to therapeutic decision-making. Expert Rev. Hematol. 2017, 10, 563–574. [Google Scholar] [CrossRef] [PubMed]
- Ravandi, F.; Walter, R.B.; Freeman, S.D. Evaluating measurable residual disease in acute myeloid leukemia. Blood Adv. 2018, 2, 1356–1366. [Google Scholar] [CrossRef] [Green Version]
- Chou, W.C.; Tang, J.L.; Wu, S.J.; Tsay, W.; Yao, M.; Huang, S.Y.; Huang, K.C.; Chen, C.Y.; Huang, C.F.; Tien, H.F. Clinical implications of minimal residual disease monitoring by quantitative polymerase chain reaction in acute myeloid leukemia patients bearing nucleophosmin (NPM1) mutations. Leukemia 2007, 21, 998–1004. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Barragan, E.; Pajuelo, J.C.; Ballester, S.; Fuster, O.; Cervera, J.; Moscardo, F.; Senent, L.; Such, E.; Sanz, M.A.; Bolufer, P. Minimal residual disease detection in acute myeloid leukemia by mutant nucleophosmin (NPM1): Comparison with WT1 gene expression. Clin. Chim. Acta 2008, 395, 120–123. [Google Scholar] [CrossRef] [PubMed]
- Bacher, U.; Badbaran, A.; Fehse, B.; Zabelina, T.; Zander, A.R.; Kroger, N. Quantitative monitoring of NPM1 mutations provides a valid minimal residual disease parameter following allogeneic stem cell transplantation. Exp. Hematol. 2009, 37, 135–142. [Google Scholar] [CrossRef] [PubMed]
- Dvorakova, D.; Racil, Z.; Jeziskova, I.; Palasek, I.; Protivankova, M.; Lengerova, M.; Razga, F.; Mayer, J. Monitoring of minimal residual disease in acute myeloid leukemia with frequent and rare patient-specific NPM1 mutations. Am. J. Hematol. 2010, 85, 926–929. [Google Scholar] [CrossRef]
- Kristensen, T.; Moller, M.B.; Friis, L.; Bergmann, O.J.; Preiss, B. NPM1 mutation is a stable marker for minimal residual disease monitoring in acute myeloid leukaemia patients with increased sensitivity compared to WT1 expression. Eur. J. Haematol. 2011, 87, 400–408. [Google Scholar] [CrossRef]
- Kronke, J.; Schlenk, R.F.; Jensen, K.O.; Tschurtz, F.; Corbacioglu, A.; Gaidzik, V.I.; Paschka, P.; Onken, S.; Eiwen, K.; Habdank, M.; 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. [Google Scholar] [CrossRef]
- Karas, M.; Steinerova, K.; Lysak, D.; Hrabetova, M.; Jungova, A.; Sramek, J.; Jindra, P.; Polivka, J.; Holubec, L. 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, 5487–5498. [Google Scholar] [CrossRef] [PubMed]
- Bill, M.; Grimm, J.; Jentzsch, M.; Kloss, L.; Goldmann, K.; Schulz, J.; Beinicke, S.; Hantschel, J.; Cross, M.; Vucinic, V.; et al. Digital droplet PCR-based absolute quantification of pre-transplant NPM1 mutation burden predicts relapse in acute myeloid leukemia patients. Ann. Hematol. 2018, 97, 1757–1765. [Google Scholar] [CrossRef] [PubMed]
- Delsing Malmberg, E.; Johansson Alm, S.; Nicklasson, M.; Lazarevic, V.; Stahlman, S.; Samuelsson, T.; Lenhoff, S.; Asp, J.; Ehinger, M.; Palmqvist, L.; 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, 409–417. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kayser, S.; Benner, A.; Thiede, C.; Martens, U.; Huber, J.; Stadtherr, P.; Janssen, J.W.; Rollig, C.; Uppenkamp, M.J.; Bochtler, T.; et al. Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia. Blood Cancer J. 2016, 6, e449. [Google Scholar] [CrossRef] [PubMed]
- Getta, B.M.; Devlin, S.M.; Levine, R.L.; Arcila, M.E.; Mohanty, A.S.; Zehir, A.; Tallman, M.S.; Giralt, S.A.; Roshal, M. Multicolor Flow Cytometry and Multigene Next-Generation Sequencing Are Complementary and Highly Predictive for Relapse in Acute Myeloid Leukemia after Allogeneic Transplantation. Biol. Blood Marrow Transpl. 2017, 23, 1064–1071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhou, Y.; Othus, M.; Walter, R.B.; Estey, E.H.; Wu, D.; Wood, B.L. Deep NPM1 Sequencing Following Allogeneic Hematopoietic Cell Transplantation Improves Risk Assessment in Adults with NPM1-Mutated AML. Biol. Blood Marrow Transpl. 2018, 24, 1615–1620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stahl, T.; Badbaran, A.; Kroger, N.; Klyuchnikov, E.; Zabelina, T.; Zeschke, S.; Schafhausen, P.; Schultz, W.; Asenova, S.; Smirnova, A.; et al. Minimal residual disease diagnostics in patients with acute myeloid leukemia in the post-transplant period: Comparison of peripheral blood and bone marrow analysis. Leuk Lymphoma 2010, 51, 1837–1843. [Google Scholar] [CrossRef] [PubMed]
- Lee, C.J.; Savani, B.N.; Mohty, M.; Gorin, N.C.; Labopin, M.; Ruggeri, A.; Schmid, C.; Baron, F.; Esteve, J.; Giebel, S.; et al. Post-remission strategies for the prevention of relapse following allogeneic hematopoietic cell transplantation for high-risk acute myeloid leukemia: Expert review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Bone Marrow Transpl. 2019, 54, 519–530. [Google Scholar]
- Meloni, G.; Mancini, M.; Gianfelici, V.; Martelli, M.P.; Foa, R.; Falini, B. Late relapse of acute myeloid leukemia with mutated NPM1 after eight years: Evidence of NPM1 mutation stability. Haematologica 2009, 94, 298–300. [Google Scholar] [CrossRef]
- Bolli, N.; Galimberti, S.; Martelli, M.P.; Tabarrini, A.; Roti, G.; Mecucci, C.; Martelli, M.F.; Petrini, M.; Falini, B. Cytoplasmic nucleophosmin in myeloid sarcoma occurring 20 years after diagnosis of acute myeloid leukaemia. Lancet Oncol. 2006, 7, 350–352. [Google Scholar] [CrossRef]
- Ivey, A.; Hills, R.K.; Simpson, M.A.; Jovanovic, J.V.; Gilkes, A.; Grech, A.; Patel, Y.; Bhudia, N.; Farah, H.; Mason, J.; et al. Assessment of Minimal Residual Disease in Standard-Risk AML. N. Engl. J. Med. 2016, 374, 422–433. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thol, F.; Kolking, B.; Damm, F.; Reinhardt, K.; Klusmann, J.H.; Reinhardt, D.; von Neuhoff, N.; Brugman, M.H.; Schlegelberger, B.; Suerbaum, S.; et al. Next-generation sequencing for minimal residual disease monitoring in acute myeloid leukemia patients with FLT3-ITD or NPM1 mutations. Genes Chromosomes Cancer 2012, 51, 689–695. [Google Scholar] [CrossRef] [PubMed]
- Martinez-Losada, C.; Serrano-Lopez, J.; Serrano-Lopez, J.; Noguera, N.I.; Garza, E.; Piredda, L.; Lavorgna, S.; Consalvo, M.A.I.; Ottone, T.; Alfonso, V.; 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. [Google Scholar] [CrossRef] [PubMed]
- Kronke, J.; Bullinger, L.; Teleanu, V.; Tschurtz, F.; Gaidzik, V.I.; Kuhn, M.W.; Rucker, F.G.; Holzmann, K.; Paschka, P.; Kapp-Schworer, S.; et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 2013, 122, 100–108. [Google Scholar] [CrossRef] [Green Version]
- Sockel, K.; Wermke, M.; Radke, J.; Kiani, A.; Schaich, M.; Bornhauser, M.; Ehninger, G.; Thiede, C.; Platzbecker, U. Minimal residual disease-directed preemptive treatment with azacitidine in patients with NPM1-mutant acute myeloid leukemia and molecular relapse. Haematologica 2011, 96, 1568–1570. [Google Scholar] [CrossRef]
- Bacher, U.; Porret, N.; Joncourt, R.; Sanz, J.; Aliu, N.; Wiedemann, G.; Jeker, B.; Banz, Y.; Pabst, T. Pitfalls in the molecular follow up of NPM1 mutant acute myeloid leukemia. Haematologica 2018, 103, e486–e488. [Google Scholar] [CrossRef]
- Schnittger, S.; Bacher, U.; Haferlach, C.; Alpermann, T.; Dicker, F.; Sundermann, J.; Kern, W.; Haferlach, T. Characterization of NPM1-mutated AML with a history of myelodysplastic syndromes or myeloproliferative neoplasms. Leukemia 2011, 25, 615–621. [Google Scholar] [CrossRef] [Green Version]
- Courville, E.L.; Wu, Y.; Kourda, J.; Roth, C.G.; Brockmann, J.; Muzikansky, A.; Fathi, A.T.; de Leval, L.; Orazi, A.; Hasserjian, R.P. Clinicopathologic analysis of acute myeloid leukemia arising from chronic myelomonocytic leukemia. Mod. Pathol. 2013, 26, 751–761. [Google Scholar] [CrossRef]
- Fernandez-Mercado, M.; Yip, B.H.; Pellagatti, A.; Davies, C.; Larrayoz, M.J.; Kondo, T.; Perez, C.; Killick, S.; McDonald, E.J.; Odero, M.D.; et al. Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics. PLoS ONE 2012, 7, e42334. [Google Scholar]
- Lindsley, R.C.; Mar, B.G.; Mazzola, E.; Grauman, P.V.; Shareef, S.; Allen, S.L.; Pigneux, A.; Wetzler, M.; Stuart, R.K.; Erba, H.P.; et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015, 125, 1367–1376. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.Y.; Cheng, W.Y.; Mao, Y.F.; Zhu, Y.M.; Liu, F.J.; Ma, T.T.; Shen, Y. Genetic alteration patterns and clinical outcomes of elderly and secondary acute myeloid leukemia. Hematol. Oncol. 2019, 37, 456–463. [Google Scholar] [CrossRef] [Green Version]
- Badar, T.; Szabo, A.; Sallman, D.; Komrojki, R.; Lancet, J.; Padron, E.; Song, J.; Hussaini, M.O. Interrogation of molecular profiles can help in differentiating between MDS and AML with MDS-related changes. Leuk Lymphoma 2020, 61, 1418–1427. [Google Scholar] [CrossRef]
- Forghieri, F.; Nasillo, V.; Paolini, A.; Bettelli, F.; Pioli, V.; Giusti, D.; Gilioli, A.; Colasante, C.; Acquaviva, G.; Riva, G.; et al. NPM1-Mutated Myeloid Neoplasms with <20% Blasts: A Really Distinct Clinico-Pathologic Entity? Int. J. Mol. Sci. 2020, 21, 8975. [Google Scholar] [CrossRef] [PubMed]
- Caudill, J.S.; Sternberg, A.J.; Li, C.Y.; Tefferi, A.; Lasho, T.L.; Steensma, D.P. C-terminal nucleophosmin mutations are uncommon in chronic myeloid disorders. Br. J. Haematol. 2006, 133, 638–641. [Google Scholar] [CrossRef]
- Oki, Y.; Jelinek, J.; Beran, M.; Verstovsek, S.; Kantarjian, H.M.; Issa, J.P. Mutations and promoter methylation status of NPM1 in myeloproliferative disorders. Haematologica 2006, 91, 1147–1148. [Google Scholar]
- Bains, A.; Luthra, R.; Medeiros, L.J.; Zuo, Z. FLT3 and NPM1 mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia. Am. J. Clin. Pathol. 2011, 135, 62–69. [Google Scholar] [CrossRef] [Green Version]
- Forghieri, F.; Paolini, A.; Morselli, M.; Bigliardi, S.; Bonacorsi, G.; Leonardi, G.; Coluccio, V.; Maccaferri, M.; Fantuzzi, V.; Faglioni, L.; et al. NPM1 mutations may reveal acute myeloid leukemia in cases otherwise morphologically diagnosed as myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. Leuk Lymphoma 2015, 56, 3222–3226. [Google Scholar] [CrossRef]
- Peng, J.; Zuo, Z.; Fu, B.; Oki, Y.; Tang, G.; Goswami, M.; Priyanka, P.; Muzzafar, T.; Medeiros, L.J.; Luthra, R.; et al. Chronic myelomonocytic leukemia with nucleophosmin (NPM1) mutation. Eur. J. Haematol. 2016, 96, 65–71. [Google Scholar] [CrossRef] [PubMed]
- Vallapureddy, R.; Lasho, T.L.; Hoversten, K.; Finke, C.M.; Ketterling, R.; Hanson, C.; Gangat, N.; Tefferi, A.; Patnaik, M.M. Nucleophosmin 1 (NPM1) mutations in chronic myelomonocytic leukemia and their prognostic relevance. Am J. Hematol. 2017, 92, E614–E618. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Montalban-Bravo, G.; Kanagal-Shamanna, R.; Sasaki, K.; Patel, K.; Ganan-Gomez, I.; Jabbour, E.; Kadia, T.; Ravandi, F.; DiNardo, C.; Borthakur, G.; et al. NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy. Blood Adv. 2019, 3, 922–933. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hwang, S.M.; Kim, S.M.; Nam, Y.; Kim, J.; Kim, S.; Ahn, Y.O.; Park, Y.; Yoon, S.S.; Shin, S.; Kwon, S.; et al. Targeted sequencing aids in identifying clonality in chronic myelomonocytic leukemia. Leuk Res. 2019, 84, 106190. [Google Scholar] [CrossRef] [PubMed]
- Patel, S.S.; Ho, C.; Ptashkin, R.N.; Sadigh, S.; Bagg, A.; Geyer, J.T.; Xu, M.L.; Prebet, T.; Mason, E.F.; Seegmiller, A.C.; et al. Clinicopathologic and genetic characterization of nonacute NPM1-mutated myeloid neoplasms. Blood Adv. 2019, 3, 1540–1545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, L.; Li, X.; Xu, F.; Wu, D.; He, Q.; Song, L.; Xiao, C.; Zhao, Y.; Zhang, Z.; Guo, J.; et al. NPM1 mutation with DNMT3A wild type defines a subgroup of MDS with particularly favourable outcomes after decitabine therapy. Br. J. Haematol. 2020, 189, 982–984. [Google Scholar] [CrossRef] [PubMed]
Mutation | Sequence | Predicted Amino Acid |
---|---|---|
Wild type (NPM 1.1) | GAT CTC TGG CAG TGG AGG AAG TCT CTT TAA GAAAATAG | -DLWOWRKSL |
Mutation A | GAT CTC TGT CTG GCA GTG GAG GAA GTC TCT TTA AGA AAA TAG | -DLCLAVEEVSLRK |
Mutation B | GAT CTC TGC ATG GCA GTG GAG GAA GTC TCT TTA AGA AAA TAG | -DLCMAVEEVSLRK |
Mutation D | GAT CTC TGC CTG GCA GTG GAG GAA GTC TCT TTA AGA AAA TAG | -DLCLAVEEVSLRK |
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Kelemen, K. The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms. Life 2022, 12, 109. https://doi.org/10.3390/life12010109
Kelemen K. The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms. Life. 2022; 12(1):109. https://doi.org/10.3390/life12010109
Chicago/Turabian StyleKelemen, Katalin. 2022. "The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms" Life 12, no. 1: 109. https://doi.org/10.3390/life12010109