NPM1 MUTATED, BCR-ABL1 POSITIVE MYELOID NEOPLASMS: REVIEW OF LITERATURE NPM1 mutated, BCR-ABL1 positive myeloid neoplasms

Main Article Content

Gianfranco Catalano
Pasquale Niscola
Cristina Banella
Daniela Diverio
Malgorzata Monika Trawinska
Stefano Fratoni
Rita Iazzoni
Paolo de Fabritiis
Elisabetta abruzzese
Nelida Ines Noguera
(*) Corresponding Author:

Abstract

Break point cluster region - Abelson (BCR-ABL1) chimeric protein and mutated Nucleophosmin (NPM1) are often present in hematological cancers, but they rarely coexist in the same disease. Both anomalies are considered founder mutations causing inhibition of differentiation and apoptosis, but BCR-ABL1 could act as a secondary mutation conferring a proliferative advantage to a pre-neoplastic clone. The 2016 World Health Organization (WHO) classification lists the provisional acute myeloid leukemia (AML) with BCR-ABL1, which must be diagnosed differentially from the rare blast phase (BP) onset of a chronic myeloid leukemia (CML), mainly because of the different therapeutic approach in the use of tyrosine kinase inhibitors (TKI). Here we review all published cases since 1975 and describe a case from our institution in order to discuss the clinical and molecular features of this rare combination, and report the latest acquisition about an occurrence that could pertain either to the rare AML BCR-ABL1 positive or the even rarer CML-BP with mutated NPM1 at onset.


Downloads month by month

Downloads

Download data is not yet available.

Article Details

References

1 Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016; 374(23):2209-2221. doi:10.1056/NEJMoa1516192.
2 Keung YK, Beaty M, Powell BL, Molnar I, Buss D, Pettenati M. Philadelphia chromosome positive myelodysplastic syndrome and acute myeloid leukemia - Retrospective study and review of literature. Leuk Research 2004; 28(6):579-86. doi:10.1016/j.leukres.2003.10.027.
3 Soupir CP, Vergilio JA, Dal Cin P, Muzikansky A, Kantarjian H, Jones D et al. Philadelphia chromosome-positive acute myeloid leukemia: A rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. Am J Clin Pathol 2007; 127(4): 642-50. doi:10.1309/B4NVER1AJJ84CTUU.
4 Cuneo A, Ferrant A, Michaux JL, Demuynck H, Boogaerts M, Louwagie A et al. Philadelphia chromosome-positive acute myeloid leukemia: Cytoimmunologic and cytogenetic features. Haematologica 1996; 81(5):423-7.
5 Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129(4): 424-447.. doi:10.1182/blood-2016-08-733196.
6 Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391-405. doi:10.1182/blood-2016-03-643544.
7 Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson G et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013; 368: 2059-74. doi:10.1056/NEJMoa1301689.
8 Papayannidis C, Sartor C, Marconi G, Fontana MC, Nanni J, Cristiano G et al. Acute myeloid leukemia mutations: Therapeutic implications. Int J Mol Sci 2019. 20: (11), doi:10.3390/ijms20112721.
9 Noguera NI, Piredda ML, Taulli R, Catalano G, Angelini G, Gaur G et al. PML/RARa inhibits PTEN expression in hematopoietic cells by competing with PU.1 transcriptional activity. Oncotarget 2016, 7: 66386-66397. doi:10.18632/oncotarget.11964.
10 Panuzzo C, Crivellaro S, Carrà G, Guerrasio A, Saglio G, Morotti A. Bcr-abl promotes pten downregulation in chronic myeloid leukemia. PLoS ONE 2014; 9: e110682. doi:10.1371/journal.pone.0110682.
11 Huret J-L, Ahmad M, Arsaban M, Jacquemot-Perbal M-C, Le Berre V, Malo A et al. Atlas of Genetics and Cytogenetics in Oncology and Haematology Staff http://AtlasGeneticsOncology.org Atlas of Genetics and Cytogenetics in Oncology and Haematology. Atlas Genet Cytogenet Oncol Haematol 2015. doi:10.1093/nar/gks1082.
12 Okuwaki M. The structure and functions of NPM1/Nucleophsmin/B23, a multifunctional nucleolar acidic protein. J Biochem. 2008; 143: 441-8. doi:10.1093/jb/mvm222.
13 Yip SP, Siu PM, Leung PHM, Zhao Y, Yung BYM. The multifunctional nucleolar protein nucleophosmin/NPM/B23 and the nucleoplasmin family of proteins. Protein Reviews 2011; 15: 213-252. doi:10.1007/978-1-4614-0514-6-10.
14 Brown P, McIntyre E, Rau R, Meshinchi S, Lacayo N, Dahl G et al. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood 2007; 110:979-85. doi:10.1182/blood-2007-02-076604.
15 Calvo KL, Ojeda MJ, Ammatuna E, Lavorgna S, Ottone T, Targovnik HM et al. Detection of the nucleophosmin gene mutations in acute myelogenous leukemia through RT-PCR and polyacrylamide gel electrophoresis. Eu J Haematol. 2009, 82: 69-72. doi:10.1111/j.1600-0609.2008.01155.x.
16 Falini B, Martelli MP, Bolli N, Sportoletti P, Liso A, Tiacci E et al. Acute myeloid leukemia with mutated nucleophosmin (NPM1): Is it a distinct entity? Blood 2011; 117: 1109-20. doi:10.1182/blood-2010-08-299990.
17 Martínez-Losada C, Serrano-López J, Serrano-López J, Noguera NI, Garza E, Piredda L 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. doi:10.3324/haematol.2018.188433.
18 Federici L, Falini B. Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization. Protein Sci. 2013; 22: 545-56. doi:10.1002/pro.2240.
19 Noguera NI, Song MS, Divona M, Catalano G, Calvo KL, García F et al. Nucleophosmin/B26 regulates PTEN through interaction with HAUSP in acute myeloid leukemia. Leukemia 2013; 27: 1037-43. doi:10.1038/leu.2012.314.
20 Colombo E, Alcalay M, Pelicci PG. Nucleophosmin and its complex network: A possible therapeutic target in hematological diseases. Oncogene 2011; 30:2595-609. doi:10.1038/onc.2010.646.
21 Colombo E, Bonetti P, Lazzerini Denchi E, Martinelli P, Zamponi R, Marine J-C et al. Nucleophosmin Is Required for DNA Integrity and p19Arf Protein Stability. Mol Cell Biol. 2005; 25(20):8874-86. doi:10.1128/mcb.25.20.8874-8886.2005.
22 Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144(1):27-40. doi:10.1016/j.cell.2010.11.055.
23 Fontana MC, Marconi G, Feenstra JDM, Fonzi E, Papayannidis C, Ghelli Luserna Di Rorá A et al. Chromothripsis in acute myeloid leukemia: Biological features and impact on survival. Leukemia 2018; 32:1609-1620. doi:10.1038/s41375-018-0035-y.
24 Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150(2):264-78. doi:10.1016/j.cell.2012.06.023.
25 Noguera NI, Catalano G, Banella C, Divona M, Faraoni I, Ottone T et al. Acute promyelocytic Leukemia: Update on the mechanisms of leukemogenesis, resistance and on innovative treatment strategies. Cancers 2019; 11(10):1591. doi:10.3390/cancers11101591.
26 Krönke J, Bullinger L, Teleanu V, Tschürtz F, Gaidzik VI, Kühn MWM et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 2013; 122(1):100-8. doi:10.1182/blood-2013-01-479188.
27 Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Trans Med 2012; 4(149):149ra118. doi:10.1126/scitranslmed.3004315.
28 Potter N, Miraki-Moud F, Ermini L, Titley I, Vijayaraghavan G, Papaemmanuil E et al. Single cell analysis of clonal architecture in acute myeloid leukaemia. Leukemia 2019; 33(5):1113-1123. doi:10.1038/s41375-018-0319-2.
29 Gilliland DG. Molecular genetics of human leukemias: New insights into therapy. Sem Hematol 2002. ; 39:6-11. doi:10.1053/shem.2002.36921.
30 Gilliland, D.G.; Griffin, J.D. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 39:6-11. doi: 10.1182/blood-2002-02-0492.
31 Bacher U, Haferlach T, Alpermann T, Zenger M, Hochhaus A, Beelen DW et al. Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations. Br J Haematol; 2011; 152(6):713-20. doi:10.1111/j.1365-2141.2010.08472.x.
32 Biernaux C, Loos M, Sels A, Huez G, Stryckmans P. Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals. Blood 1995; 86: 3118-22.
33 Ismail SI, Naffa RG, Yousef AMF, Ghanim MT. Incidence of bcr-abl fusion transcripts in healthy individuals. Med Rep. 2014; 9: 1271-6. doi:10.3892/mmr.2014.1951.
34 Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood 2005; 106(8):2854-61. doi:10.1182/blood-2005-04-1733.
35 Verhaak RGW, Goudswaard CS, Van Putten W, Bijl MA, Sanders MA, Hugens W 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. doi:10.1182/blood-2005-05-2168.
36 Palmisano M, Grafone T, Ottaviani E, Testoni N, Baccarani M, Martinelli G. NPM1 mutations are more stable than FLT3 mutations during the course of disease in patients with acute myeloid leukemia. Haematologica 2007; 92(9):1268-9. doi:10.3324/haematol.11202.
37 Konoplev S, Yin CC, Kornblau SM, Kantarjian HM, Konopleva M, Andreeff M et al. Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia. Leuk Lymphoma 2013; 54: 138-44. doi:10.3109/10428194.2012.701739.
38 Reboursiere E, Chantepie S, Gac AC, Reman O. Rare but authentic Philadelphia-positive acute myeloblastic leukemia: Two case reports and a literature review of characteristics, treatment and outcome. Hematology/ Oncology and Stem Cell Ther. 2014, 8(1):28-33. doi:10.1016/j.hemonc.2014.09.002.
39 Mariotti B, Meconi F, Palmieri R, De Bellis E, Lavorgna S, Ottone T et al. Acute Myeloid Leukemia with Concomitant BCR-ABL and NPM1 Mutations. Case Rep Hematol. 2019; 6707506. doi:10.1155/2019/6707506.
40 Castagnetti F, Gugliotta G, Breccia M, Iurlo A, Levato L, Albano F et al. The BCR-ABL1 transcript type influences response and outcome in Philadelphia chromosome-positive chronic myeloid leukemia patients treated frontline with imatinib. Am J Hematol. 2017; 92(8):797-805. doi:10.1002/ajh.24774.
41 Neuendorff NR, Burmeister T, Dörken B, Westermann J. BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features. Ann Hematol. 2016; 95: 1211-21. doi:10.1007/s00277-016-2721-z.
42 Jain P, Kantarjian HM, Ghorab A, Sasaki K, Jabbour EJ, Nogueras Gonzalez G et al. Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 2017; 123(22):4391-4402. doi:10.1002/cncr.30864.
43 Gabert J, Beillard E, van der Velden VHJ, Bi W, Grimwade D, Pallisgaard N et al. Standardization and quality control studies of ‘real time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - A Europe Against Cancer Program. Leukemia 2003; 17: 2318–2357. doi:10.1038/sj.leu.2403135.
44 Ammatuna E, Noguera NI, Zangrilli D, Curzi P, Panetta P, Bencivenga P et al. Rapid detection of nucleophosmin (NPM1) mutations in acute myeloid leukemia by denaturing HPLC. Clin Chem 2005, 51: 2165-2167. doi:10.1373/clinchem.2005.055707.
45 Gorello P, Cazzaniga G, Alberti F, Dell’Oro MG, Gottardi E, Specchia G et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations. Leukemia 2006; 20: 1103-1108. doi:10.1038/sj.leu.2404149.
46 Reid AG, De Melo VA, Elderfield K, Clark I, Marin D, Apperley J et al. Phenotype of blasts in chronic myeloid leukemia in blastic phase-Analysis of bone marrow trephine biopsies and correlation with cytogenetics. Leuk Research 2009, 33: 418-425.
47 Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002; 2: 117-25. doi:10.1016/S1535-6108(02)00096-X.
48 Nacheva EP, Grace CD, Brazma D, Gancheva K, Howard-Reeves J, Rai L et al. Does BCR/ABL1 positive Acute Myeloid Leukaemia Exist?. Br J Haematol. 2013; 161: 541-50. doi:10.1111/bjh.12301.
49 Atfy M, Al Azizi NMA, Elnaggar AM. Incidence of Philadelphia-chromosome in acute myelogenous leukemia and biphenotypic acute leukemia patients: And its role in their outcome. Leuk Research 2011. 35: 1339-44. doi:10.1016/j.leukres.2011.04.011.
50 Varma S, Varma N, Malhotra P, Narang V, Sachdeva MU, Bose P. Immunophenotyping in Chronic Myeloid Leukemia Blast Crisis: Looking beyond Morphology. J Postgrad Med Edu Res. 2016; 50: 181-184.52. doi:10.5005/jp-journals-10028-1215.
51 Soverini S, Bassan R, Lion T. Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: Recent advances and remaining challenges. J Hematol Oncol. 2019;12(1):39. doi:10.1186/s13045-019-0729-2.
52 Klco JM, Miller CA, Griffith M, Petti A, Spencer DH, Ketkar-Kulkarni S et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 2015; 314: 811–822. doi:10.1001/jama.2015.9643.
53 Wang F, Chan LWC, Tsui NBY, Wong SCC, Siu PM, Yip SP et al. Coexpression pattern analysis of NPM1-associated genes in chronic myelogenous leukemia. Biomed Res Int. 2015; 2015: 1-9. doi:10.1155/2015/610595.
54 Chan LWC, Lin X, Yung G, Lui T, Chiu YM, Wang F et al. Novel structural co-expression analysis linking the NPM1-associated ribosomal biogenesis network to chronic myelogenous leukemia. Sci Rep 2015; 5: 10973. doi:10.1038/srep10973.
55 Quintás-Cardama A, Kantarjian H, Cortes J. Basophilic Blast Phase (B-BP) of Chronic Myelogenous Leukemia (CML). Blood 2007; 110: 4562.doi:10.1182/blood.v110.11.4562.4562.
56 Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999; 340:1330-40. doi:10.1056/NEJM199904293401706.
57 Kadam PR, Nanjangud GJ, Advani SH, Nair C, Banavali S, Gopal R et al. Chromosomal characteristics of chronic and blastic phase of chronic myeloid leukemia. A study of 100 patients in India. Cancer Genet Cytogenet. 1991; 51:167-81. doi:10.1016/0165-4608(91)90129-I.
58 Khalidi HS, Brynes RK, Medeiros LJ, Chang KL, Slovak ML, Snyder DS et al. The immunophenotype of blast transformation of chronic myelogenous leukemia: A high frequency of mixed lineage phenotype in ‘lymphoid’ blasts and a comparison of morphologic, immunophenotypic, and molecular findings. Mod Pathol. 1998; 11: 1211-21.
59 Branford S, Kim DDH, Apperley JF, Eide CA, Mustjoki S, Ong ST et al. Laying the foundation for genomically-based risk assessment in chronic myeloid leukemia. Leukemia. 2019; 33: 1835-1850. doi:10.1038/s41375-019-0512-y.
60 Moarii M, Papaemmanuil E. Classification and risk assessment in AML: Integrating cytogenetics and molecular profiling. 2017; 2017: 37-44. doi:10.1182/asheducation-2017.1.37.
61 Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 366: 1079-89. doi:10.1056/NEJMoa1112304.
62 Vitale C, Lu X, Abderrahman B, Takahashi K, Ravandi F, Jabbour E. t(9;22) as secondary alteration in core-binding factor de novo acute myeloid leukemia. Am J Hematol 2015; 90:E211-2. doi:10.1002/ajh.24143.
63 Salem A, Loghavi S, Tang G, Huh YO, Jabbour EJ, Kantarjian H et al. Myeloid neoplasms with concurrent BCR-ABL1 and CBFB rearrangements: A series of 10 cases of a clinically aggressive neoplasm. Am J Hematol. 2017; 92: 520-528. doi:10.1002/ajh.24710.
64 Lessard M, Le Prisé PY. Cytogenetic studies in 56 cases with Ph1-positive hematologic disorders. Cancer Genet Cytogenet. 1982; 5: 37-49. doi:10.1016/0165-4608(82)90039-5.
65 Piccaluga PP, Sabattini E, Bacci F, Agostinelli C, Righi S, Salmi F et al. Cytoplasmic mutated nucleophosmin (NPM1) in blast crisis of chronic myeloid leukaemia. Leukemia 2009; 23: 1370-1. doi:10.1038/leu.2009.95.

Most read articles by the same author(s)

1 2 3 > >>