Molecular Genetic Testing for Acute Myeloid Leukemia
Authors:
V. Janečková; L. Semerád; I. Ježíšková; D. Dvořáková; M. Čulen; Z. Šustková; J. Mayer; Z. Ráčil
Authors place of work:
Interní hematologická a onkologická klinika LF MU a FN Brno
Published in the journal:
Klin Onkol 2016; 29(6): 411-418
Category:
Review
doi:
https://doi.org/10.14735/amko2016411
Summary
Background:
Acute myeloid leukemia (AML) is a clinically complex and very heterogeneous disease at the molecular level. Conventional cytogenetic analysis and FISH (fluorescence in situ hybridization) tests provide important information about the biological and clinical background of the disease and enable the classification of AML patients into three risk groups. However, up to half of patients have normal cytogenetics. Determining prognosis and treatment strategies in this group of patients is challenging. The development of molecular genetic methods, including next generation sequencing in the last decade, has led to the discovery of a number of recurrent mutations that have contributed to increasing the accuracy of prognosis of those patients with cytogenetically normal AML. Besides the prognostic value of these mutations, they may also be used to monitor minimal residual disease during and after treatment of AML and additionally constitute potential targets for the development of new therapeutic agents. The importance of molecular genetic testing of all patients with AML is highlighted by the WHO classification of 2008 in which subgroups of AML are purely defined by molecular genetics markers.
Aim:
In this article, we provide an overview of the most significant mutations in patients with cytogenetically normal AML. We describe their significance for prognosis, their importance in monitoring minimal residual disease, and their potential for the development of new targeted therapies. Further, we briefly draw attention to the significance of gene mutation accumulation in clonal disease development and how it affects the time of AML relapse.
Keywords:
acute myeloid leukemia – genetics – mutation – prognosis – minimal residual disease – clonal evolution
This work was supported by the program project of the Czech Ministry of Health reg. No. 15-25809A and by the project of Masaryk University, Brno MUNI/A/1028/2016.
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted:
8. 9. 2016
Accepted:
30. 9. 2016
Zdroje
1. Grimwade D, Walker H, Oliver F et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukaemia working parties. Blood 1998; 92 (7): 2322–2333.
2. Wakita S, Yamaguchi H, Ueki T et al. Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia. Leukemia 2016; 30 (3): 545–554. doi: 10.1038/leu.2015.288.
3. Swerdlow SH, Campo E, Harris NL et al. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon (France): IARC 2008.
4. Döhner H, Estey EH, Amadori S et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115 (3): 453–474. doi: 10.1182/blood-2009-07-235358.
5. 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 (20): 2391–2405. doi: 10.1182/blood-2016-03-643544.
6. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100 (5): 1532–1542.
7. Takahashi S. Current findings for recurring mutations in acute myeloid leukemia. J Hematol Oncol 2011; 4: 36. doi: 10.1186/1756-8722-4-36.
8. Welch JS, Ley TJ, Link DC et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150 (2): 264–278. doi: 10.1016/j.cell.2012.06.023.
9. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368 (22): 2059–2074. doi: 10.1056/NEJMoa1301689.
10. Ding L, Ley TJ, Larson DE et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012; 481 (7382): 506–510. doi: 10.1038/nature10738.
11. Shlush LI, Zandi S, Mitchell A et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506 (7488): 328–333. doi: 10.1038/nature13038.
12. Xie M, Lu C, Wang J et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20 (12): 1472–1478. doi: 10.1038/nm.3733.
13. Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood 2016; 127 (1): 29–41. doi: 10.1182/blood-2015-07-604496.
14. Wong TN, Miller CA, Klco JM et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 2016; 127 (7): 893–897. doi: 10.1182/blood-2015-10-677021.
15. Greaves M, Maley CC. Clonal evolution in cancer. Nature 2012; 481 (7381): 306–313.
16. Grimwade D, Walker H, Harrison G et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1,065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001; 98 (5): 1312–1320.
17. Meyer SC, Levine RL. Translational implications of somatic genomics in acute myeloid leukaemia. Lancet Oncol 2014; 15 (9): e382–e394. doi: 10.1016/S1470-2045 (14) 70008-7.
18. Marcucci G, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 2011; 29 (5): 475–486. doi: 10.1200/JCO.2010.30.2554.
19. Klco JM, Miller CA, Griffith M et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA 2015; 314 (8): 811–822. doi: 10.1001/jama.2015.9643.
20. 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 AML 10 and 12 trials. Blood 2001; 98 (6): 1752–1759.
21. Nakao M, Yokota S, Iwai T et al. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia 1996; 10 (12): 1911–1918.
22. 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): 4326–4335.
23. Yamamoto Y, Kiyoi H, Nakano Y et al. Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies. Blood 2001; 97 (8): 2434–2439.
24. Cloos J, Goemans BF, Hess CJ et al. Stability and prognostic influence of FLT3 mutations in paired initial and relapsed AML samples. Leukemia 2006; 20 (7): 1217–1220.
25. Li J, Zhang X, Sejas DP et al. Negative regulation of p53 by nucleophosmin antagonizes stress-induced apoptosis in human normal and malignant hematopoietic cells. Leuk Res 2005; 29 (12): 1415–1423.
26. 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): 254–266.
27. Krönke J, Bullinger L, Teleanu V et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 2013; 122 (1): 100–108. doi: 10.1182/blood-2013-01-479188.
28. 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): 4011–4020.
29. Pabst T, Mueller BU, Zhang P et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet 2001; 27 (3): 263–270.
30. Fasan A, Haferlach C, Alpermann T et al. The role of different genetic subtypes of CEBPA mutated AML. Leukemia 2014; 28 (4): 794–803. doi: 10.1038/leu.2013.273.
31. Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA et al. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009; 113 (13): 3088–3091. doi: 10.1182/blood-2008-09-179895.
32. Green CL, Koo KK, Hills RK et al. Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol 2010; 28 (16): 2739–2747. doi: 10.1200/JCO.2009.26.2501.
33. Corces-Zimmerman MR, Hong WJ, Weissman IL et al. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci U S A 2014; 111 (7): 2548–2553. doi: 10.1073/pnas.1324297111.
34. Genovese G, Kähler AK, Handsaker RE et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371 (26): 2477–2487. doi: 10.1056/NEJMoa1409405.
35. Challen GA, Sun D, Jeong M et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat Genet 2012; 44 (1): 23–31. doi: 10.1038/ng.1009.
36. Yan XJ, Xu J, Gu ZH et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 2011; 43 (4): 309–315. doi: 10.1038/ng.788.
37. Gale RE, Lamb K, Allen C et al. Simpson’s paradox and the impact of different dnmt3a mutations on outcome in younger adults with acute myeloid leukemia. J Clin Oncol 2015; 33 (18): 2072–2083. doi: 10.1200/JCO.2014.59. 2022.
38. Thol F, Damm F, Lüdeking A et al. Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 2011; 29 (21): 2889–2896. doi: 10.1200/JCO.2011.35.4894.
39. Ley TJ, Ding L, Walter MJ et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363 (25): 2424–2433. doi: 10.1056/NEJMoa1005143.
40. Marcucci G, Metzeler KH, Schwind S et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol 2012; 30 (7): 742–750. doi: 10.1200/JCO.2011.39.2092.
41. Gaidzik VI, Schlenk RF, Paschka P et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: results of the AML Study Group (AMLSG). Blood 2013; 121 (23): 4769–4777. doi: 10.1182/blood-2012-10-461624.
42. 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 (22): 3636–3643. doi: 10.1200/JCO.2010.28.3762.
43. Mardis ER, Ding L, Dooling DJ et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361 (11): 1058–1066. doi: 10.1056/NEJMoa0903840.
44. Marcucci G, Maharry K, Wu YZ et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010; 28 (14): 2348–2355. doi: 10.1200/JCO.2009.27. 3730.
45. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 2010; 102 (13): 932–941. doi: 10.1093/jnci/djq187.
46. Metzeler KH, Maharry K, Radmacher MD et al. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2011; 29 (10): 1373–1381. doi: 10.1200/JCO.2010.32.7742.
47. Figueroa ME, Abdel-Wahab O, Lu C et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010; 18 (6): 553–567. doi: 10.1016/j.ccr.2010.11.015.
48. Schnittger S, Haferlach C, Ulke M et al. IDH1 mutations are detected in 6.6% of 1414 AML patients and are associated with intermediate risk karyotype and unfavorable prognosis in adults younger than 60 years and unmutated NPM1 status. Blood 2010; 116 (25): 5486–5496. doi: 10.1182/blood-2010-02-267955.
49. Patel JP, Gönen M, Figueroa ME et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366 (12): 1079–1089. doi: 10.1056/NEJMoa1112304.
50. Ko M, Huang Y, Jankowska AM et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 2010; 468 (7325): 839–843. doi: 10.1038/nature09586.
51. Busque L, Patel JP, Figueroa ME et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012; 44 (11): 1179–1181. doi: 10.1038/ng.2413.
52. Chou WC, Chou SC, Liu CY et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011; 118 (14): 3803–3810. doi: 10.1182/blood-2011-02-339747.
53. Gaidzik VI, Paschka P, Späth D et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group. J Clin Oncol 2012; 30 (12): 1350–1357. doi: 10.1200/JCO.2011.39.2886.
54. Lee SW, Cho YS, Na JM et al. ASXL1 represses retinoic acid receptor-mediated transcription through associating with HP1 and LSD1. J Biol Chem 2010; 285 (1): 18–29. doi: 10.1074/jbc.M109.065862.
55. Gelsi-Boyer V, Trouplin V, Adélaïde J et al. Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009; 145 (6): 788–800. doi: 10.1111/j.1365- 2141.2009.07697.x.
56. Abdel-Wahab O, Manshouri T, Patel J et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias. Cancer Res 2010; 70 (2): 447–452. doi: 10.1158/0008-5472.CAN-09-3783.
57. Schnittger S, Eder C, Jeromin S et al. ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 2013; 27 (1): 82–91. doi: 10.1038/leu.2012.262.
58. Chou WC, Huang HH, Hou HA et al. Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations. Blood 2010; 116 (20): 4086–4094. doi: 10.1182/blood-2010-05-283291.
59. Rocquain J, Carbuccia N, Trouplin V et al. Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias. BMC Cancer 2010; 10: 401. doi: 10.1186/1471-2407-10-401.
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