Mutations of the RAS family in patients with acute myeloid leukaemia
Authors:
A. Ďuriníková 1,2; A. Folta 2; M. Čulen 1,2,3; Z. Herudková 1,2; D. Al Tukmachi 3; J. Mayer 1,2,3; I. Ježíšková 1,2
Authors‘ workplace:
Lékařská fakulta, Masarykova univerzita, Brno
1; Interní hematologická a onkologická klinika, Fakultní nemocnice Brno, Brno
2; CEITEC – Středoevropský technologický institut, Masarykova univerzita, Brno
3
Published in:
Transfuze Hematol. dnes,25, 2019, No. 4, p. 331-338.
Category:
Review/Educational Papers
Overview
Somatic mutations in RAS (rat sarcoma viral oncogene homolog) proto-oncogenes lead to constitutive activation of RAS signalling pathways impacting cellular proliferation, differentiation and apoptosis. RAS mutations are detected in approximately one fifth of patients with acute myeloid leukaemia (AML). Typically, the aberrations are missense heterozygous point mutations localized in codons G12, G13 and Q61 in exons 2 and 3, respectively. In AML, NRAS is the most frequently mutated gene of the RAS family. Simultaneously mutated NRAS and KRAS genes in one patient are possible, but rare. In approximately 10% of AML patients, multiple NRAS mutations are detected. The RAS mutations occur with higher frequency in AML patients with chromosomal aberrations inv(16)/t(16;16), t(8;21), inv(3)/t(3;3). In patients with normal karyotype, the RAS genes are frequently co-mutated with the NPM1 and DNMT3A genes. Most of the large cohort studies did not demonstrate any implication of RAS mutations on overall survival, and its occurrence was not significantly associated with any clinical parameters. During leukaemogenesis, RAS mutations play a role as late secondary events supporting increased proliferation of AML subclones.
The aim of this work is to summarize the current knowledge about the RAS gene family and its significance in patients with AML.
Keywords:
acute myeloid leukaemia – AML – RAS – mutations
Sources
1. 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.
2. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016;374(23):2209–2221.
3. Metzeler KH, Herold T, Rothenberg-Thurley M, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood 2016;128(5):686–698.
4. Ley TJ, Miller C, Ding L, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368(22):2059–2074.
5. Shin SY, Lee ST, Kim HJ, et al. Mutation profiling of 19 candidate genes in acute myeloid leukemia suggests significance of DNMT3A muta-tions. Oncotarget 2016;7(34):54825–54837.
6. Reuter CW, Krauter J, Onono FO, et al. Lack of noncanonical RAS mutations in cytogenetically normal acute myeloid leukemia. Ann Hematol 2014;93(6):977–982.
7. Dunna NR, Vuree S, Anuradha C, et al. NRAS mutations in de novo acute leukemia: prevalence and clinical significance. Indian J Biochem Biophys 2014;51(3):207–210.
8. Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 2008;358(18):1909–1918.
9. Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S. Implications of NRAS mutations in AML: a study of 2502 patients. Blood 2006;107(10):3847–3853.
10. Bowen DT, Frew ME, Hills R, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years. Blood 2005;106(6):2113–2119.
11. Neubauer A, Dodge RK, George SL, et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 1994;83(6):1603–1611.
12. Farr CJ, Saiki RK, Erlich HA, McCormick F, Marshall CJ. Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes. Proc Natl Acad Sci U S A 1988;85(5):1629–1633.
13. Krauth MT, Eder C, Alpermann T, et al. High number of additional genetic lesions in acute myeloid leukemia with t(8;21)/RUNX1-RUNX1T1: frequency and impact on clinical outcome. Leukemia 2014;28:1449.
14. Preston R, Däbritz J, Hänfler J, Oettle H. Mutational analysis of K-ras codon 12 in blood samples of patients with acute myeloid leukemia. Leuk Res 2010;34(7):883–891.
15. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007;7(4):295–308.
16. Illmer T, Thiede C, Fredersdorf A, et al. Activation of the RAS pathway is predictive for a chemosensitive phenotype of acute myelogenous leukemia blasts. Clin Cancer Res 2005;11(9):3217–3224.
17. Chang EH, Gonda MA, Ellis RW, Scolnick EM, Lowy DR. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc Natl Acad Sci U S A 1982;79(16):4848–4852.
18. Hall A, Marshall CJ, Spurr NK, Weiss RA. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature 1983;303(5916):396–400.
19. Malumbres M, Barbacid M. RAS oncogenes: the first 30 years. Nat Rev Cancer 2003;3(6):459–465.
20. Mitin N, Rossman KL, Der CJ. Signaling interplay in Ras superfamily function. Curr Biol 2005;15(14):R563–R574.
21. Pruitt K, Der CJ. Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett 2001;171(1):1–10.
22. Lim KH, Baines AT, Fiordalisi JJ, et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell 2005;7(6):533–545.
23. Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta 2007;1773(8):1177–1195.
24. Forbes SA, Bindal N, Bamford S, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2011;39(Database issue):D945–D950.
25. Adjei AA. Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 2001;93(14):1062–1074.
26. Colicelli J. Human RAS superfamily proteins and related GTPases. Sci STKE 2004;2004(250):RE13.
27. Gambke C, Hall A, Moroni C. Activation of an N-ras gene in acute myeloblastic leukemia through somatic mutation in the first exon. Proc Natl Acad Sci U S A 1985;82(3):879–882.
28. Bashey A, Gill R, Levi S, et al. Mutational activation of the N-ras oncogene assessed in primary clonogenic culture of acute myeloid leukemia (AML): implications for the role of N-ras mutation in AML pathogenesis. Blood 1992;79(4):981–989.
29. Welch JS. Mutation position within evolutionary subclonal architecture in AML. Semin Hematol 2014;51(4):273–281.
30. Martignoles JA, Delhommeau F, Hirsch P. Genetic Hierarchy of acute myeloid leukemia: from clonal hematopoiesis to molecular residual disease. Int J Mol Sci 2018;19(12).
31. Tyner JW, Erickson H, Deininger MW, et al. High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients. Blood 2009;113(8):1749–1755.
32. Kubo K, Naoe T, Kiyoi H, et al. Clonal analysis of multiple point mutations in the N-ras gene in patients with acute myeloid leukemia. Jpn J Cancer Res 1993;84(4):379–387.
33. Krönke J, Bullinger L, Teleanu V, et al. Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia. Blood 2013;122(1):100–108.
34. Nakamura H, Inokuchi K, Yamaguchi H, Dan K. Abnormalities of p51, p53, FLT3 and N-ras genes and their prognostic value in relapsed acute myeloid leukemia. J Nippon Med Sch 2004;71(4):270–278.
35. Nakano Y, Kiyoi H, Miyawaki S, et al. Molecular evolution of acute myeloid leukaemia in relapse: unstable N-ras and FLT3 genes compared with p53 gene. Br J Haematol 1999;104(4):659–664.
36. Kuchenbauer F, Schnittger S, Look T, et al. Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO. Br J Haematol 2006;134(6):616–619.
37. Zuber J, Radtke I, Pardee TS, et al. Mouse models of human AML accurately predict chemotherapy response. Genes Dev 2009;23(7):877–889.
38. Schessl C, Rawat VP, Cusan M, et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest 2005;115(8):2159–2168.
39. Zhao S, Zhang Y, Sha K, et al. KRAS (G12D) cooperates with AML1/ETO to initiate a mouse model mimicking human acute myeloid leukemia. Cell Physiol Biochem 2014;33(1):78–87.
40. Valk PJ, Bowen DT, Frew ME, Goodeve AC, Löwenberg B, Reilly JT. Second hit mutations in the RTK/RAS signaling pathway in acute myeloid leukemia with inv(16). Haematologica 2004;89(1):106.
41. Lugthart S, Gröschel S, Beverloo HB, et al. Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia. J Clin Oncol 2010;28(24):3890–3898.
42. Haferlach C, Bacher U, Haferlach T, et al. The inv(3)(q21q26)/t(3;3)(q21;q26) is frequently accompanied by alterations of the RUNX1, KRAS and NRAS and NF1 genes and mediates adverse prognosis both in MDS and in AML: a study in 39 cases of MDS or AML. Leukemia 2011;25(5):874–877.
43. Hinai AA, Valk PJ. Review: Aberrant EVI1 expression in acute myeloid leukaemia. Br J Haematol 2016;172(6):870–878.
44. Kataoka K, Kurokawa M. Ecotropic viral integration site 1, stem cell self-renewal and leukemogenesis. Cancer Sci 2012;103(8):1371–1377.
45. Gröschel S, Sanders MA, Hoogenboezem R, et al. Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways. Blood 2015;125(1):133–139.
46. Lavallée VP, Gendron P, Lemieux S, D‘Angelo G, Hébert J, Sauvageau G. EVI1-rearranged acute myeloid leukemias are characterized by distinct molecular alterations. Blood 2015;125(1):140–143.
47. Goemans BF, Zwaan CM, Miller M, et al. Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 2005;19:1536.
48. Boissel N, Leroy H, Brethon B, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 2006;20:965.
49. Wang M, Yang C, Zhang L, Schaar DG. Molecular mutations and their cooccurrences in cytogenetically normal acute myeloid leukemia. Stem Cells Int 2017;2017:6962379.
50. Hiorns LR, Cotter FE, Young BD. Co-incident N and K ras gene mutations in a case of AML, restricted to differing cell lineages. Br J Haematol 1989;73(2):165–167.
51. Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S. Impact of FLT3 mutations and promyelocytic leu-kaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Haematol 2005;130(2):196–202.
52. Gale RE, Hills R, Pizzey AR, et al. Relationship between FLT3 muta-tion status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005;106(12):3768–3776.
53. Stirewalt DL, Kopecky KJ, Meshinchi S, et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001;97(11):3589–3595.
54. Kadia TM, Kantarjian H, Kornblau S, et al. Clinical and proteomic characterization of acute myeloid leukemia with mutated RAS. Cancer 2012;118(22):5550–5559.
55. Yang X, Qian J, Sun A, et al. RAS mutation analysis in a large cohort of Chinese patients with acute myeloid leukemia. Clin Biochem 2013;46(7–8):579–583.
56. Liu X, Ye Q, Zhao XP, et al. RAS mutations in acute myeloid leukaemia patients: A review and meta-analysis. Clin Chim Acta 2019;489:254–260.
Labels
Haematology Internal medicine Clinical oncologyArticle was published in
Transfusion and Haematology Today
2019 Issue 4
Most read in this issue
- Genome editing using the CRISPR/Cas9 system and its application in haematology
- Characteristics and results of the treatment of patients with acute myeloid leukaemia ≥ 60 years – data from the CELL DATOOL AML database
- Mutations of the RAS family in patients with acute myeloid leukaemia
- Complex mechanisms of action of „BCR signalling“ inhibitors and development of resistance to this targeted therapy in chronic lymphocytic leukaemia