NPM1 and FLT3-ITD/TKD Gene Mutations in Acute Myeloid Leukemia
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Abstract
Background: A number of mutations have been reported to occur in patients with acute myeloid leukemia (AML), of which NPM1 and FLT3 gene mutations are the commonest and have important diagnostic and therapeutic implications, respectively.
Material and Methods: Molecular testing for NPM1 and FLT3 genes was performed in 92 de-novo AML patients. The frequency and characteristics of NPM1 and FLT3 mutations were analyzed.
Results: Nucleophosmin 1(NPM1) and FMS-like tyrosine kinase 3 (FLT3) mutations were seen in 22.8% and 16.3% of patients, respectively. Amongst FLT3 mutations, FLT3-ITD mutation was seen in 8.7% cases, FLT3-TKD in 5.4%, and FLT3-ITD+TKD in 2.2% cases. Certain associations between the gene mutations and clinical characteristics were found, including in NPM1 mutated group- female preponderance, the higher incidence in M4/M5 categories and decreased expression of CD34 and HLA-DR; and in FLT3-ITD mutated group- higher age of presentation, higher total leucocyte count and blast percentage.
Conclusion- AML patients with NPM1 and FLT3 mutations have differences in clinical and hematological features, which might represent their different molecular mechanisms in leukemogenesis. The frequency of NPM1 and FLT3 mutations in this study was comparable to reports from Asian countries but lower than that reported from western countries. However, as the number of patients in the study was less, a larger number of patients need to be studied to corroborate these findings
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17. Bianchini M, Ottaviani E, Grafone T, et al. Rapid detection of Flt3 mutations in acute myeloid leukemia patients by denaturing HPLC. Clin Chem. 2003; 49(10):1642–50.
18. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML10 and 12 trials. Blood. 2001; 98(6):1752-9.
19. Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood. 2008; 111(5): 2527-37.
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21. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002; 99(12):4326-35.
22. Lazenby M, Gilkes AF, Marrin C, et al. The prognostic relevance of FLT3 and NPM1 mutations on older patients treated intensively or non-intensively: a study of 1312 patients in the UK NCRI AML16 trial. Leukemia. 2014; 28(10): 1953–9.
23. Juliusson G, Jadersten 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(6): 1094-1101.
24. Chauhan PS, Ihsan R, Singh LC, et al. Mutation of NPM1 and FLT3 genes in acute myeloid leukemia and their association with clinical and immunophenotypic features. Dis Markers. 2013; 35(5):581-8.
25. Boonthimat C, Thongnoppakhun W, Auewarakul CU. Nucleophosmin mutation in Southeast Asian acute myeloid leukemia: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations. Haematologica. 2008; 93(10): 1565–9.
26. Ruan GR, Li JL, Qin YZ, et al. Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia. Ann Hematol. 2009; 88(2): 159–66.
27. Elyamany G, Awad M, Fadalla K, et al. Frequency and prognostic pelevance of FLT3 mutations in Saudi acute myeloid leukemia patients. Adv Hematol. 2014; 2014:141360.
28. Sazawal S, Singh N, Jain S, et al. NPM1 and FLT3 mutations in acute myeloid leukemia with normal karyotype: Indian perspective. Indian J Pathol Microbiol. 2017; 60(3):355-359.
29. 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(12):3740-6.
2. Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-66.
3. Nerlov C. CEBP/alpha mutations in acute myeloid leukaemias. Nat Rev Cancer. 2004;4(5):394-400.
4. Mendler JH, Maharry K, Radmacher MD, et al. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J Clin Oncol. 2012; 30(25):3109- 18.
5. Patnaik MM. The importance of FLT3 mutational analysis in acute myeloid leukemia. Leuk Lymphoma. 2018;59(10):2273-2286.
6. Brown P, McIntyre E, Rau R, et al. The incidence and clinical significance of nucleophosmin mutations in childhood AML. Blood. 2007; 110(3): 979-85.
7. Thiede C, Koch S, Creutzig E, et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). Blood. 2006; 107(10):4011-20.
8. Haferlach C, Mecucci C, Schnittger S, et al. AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features. Blood. 2009; 114(14):3024-32.
9. Falini B, Bolli N, Liso A, et al. Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications. Leukemia. 2009; 23(10):1731-43.
10. Boissel N, Renneville A, Biggio V, et al. Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype. Blood. 2005; 106(10):3618-20.
11. Smith CC, Wang Q, Chin CS, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012; 485(7397):260–3.
12. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017; 377(5)454–64.
13. Zarrinkar PP, Gunawardane RN, Cramer MD, et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood. 2009; 114(4):2984–92.
14. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424–447.
15. Pakakasama S, Kajanachumpol S, Kanjanapongkul S, et al. Simple multiplex RT-PCR for identifying common fusion transcripts in childhood acute leukemia. Int J Lab Hematol. 2008; 30(4):286-91.
16. Noguera NI, Ammatuna E, Zangrilli D, et al. Simultaneous detection of NPM1 and FLT3-ITD mutations by capillary electrophoresis in acute myeloid leukemia. Leukemia. 2005; 19(8): 1479–82.
17. Bianchini M, Ottaviani E, Grafone T, et al. Rapid detection of Flt3 mutations in acute myeloid leukemia patients by denaturing HPLC. Clin Chem. 2003; 49(10):1642–50.
18. Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML10 and 12 trials. Blood. 2001; 98(6):1752-9.
19. Bacher U, Haferlach C, Kern W, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood. 2008; 111(5): 2527-37.
20. Rastogi P, Naseem S, Varma N, et al. Nucleophosmin mutation in de-novo acute myeloid leukemia. Asia Pacific J Clin Oncol 2016; 12(1): 77-85.
21. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002; 99(12):4326-35.
22. Lazenby M, Gilkes AF, Marrin C, et al. The prognostic relevance of FLT3 and NPM1 mutations on older patients treated intensively or non-intensively: a study of 1312 patients in the UK NCRI AML16 trial. Leukemia. 2014; 28(10): 1953–9.
23. Juliusson G, Jadersten 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(6): 1094-1101.
24. Chauhan PS, Ihsan R, Singh LC, et al. Mutation of NPM1 and FLT3 genes in acute myeloid leukemia and their association with clinical and immunophenotypic features. Dis Markers. 2013; 35(5):581-8.
25. Boonthimat C, Thongnoppakhun W, Auewarakul CU. Nucleophosmin mutation in Southeast Asian acute myeloid leukemia: eight novel variants, FLT3 coexistence and prognostic impact of NPM1/FLT3 mutations. Haematologica. 2008; 93(10): 1565–9.
26. Ruan GR, Li JL, Qin YZ, et al. Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia. Ann Hematol. 2009; 88(2): 159–66.
27. Elyamany G, Awad M, Fadalla K, et al. Frequency and prognostic pelevance of FLT3 mutations in Saudi acute myeloid leukemia patients. Adv Hematol. 2014; 2014:141360.
28. Sazawal S, Singh N, Jain S, et al. NPM1 and FLT3 mutations in acute myeloid leukemia with normal karyotype: Indian perspective. Indian J Pathol Microbiol. 2017; 60(3):355-359.
29. 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(12):3740-6.
| Files | ||
| Issue | Vol 15, No 1 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v15i1.5246 | |
| Keywords | ||
| Acute myeloid leukemia; Nucleophosmin 1(NPM1) mutation; FMS-like tyrosine kinase 3 (FLT3) mutation | ||
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How to Cite
1.
Naseem S, Binota J, Virk H, Varma N, Varma S, Malhotra P. NPM1 and FLT3-ITD/TKD Gene Mutations in Acute Myeloid Leukemia. Int J Hematol Oncol Stem Cell Res. 2021;15(1):15-26.
