Clinical, hematological and molecular-genetic features of acute myeloid leukemia with mutations in FLT3, CKIT, NRAS and NPM1
https://doi.org/10.18821/0234-5730-2016-61-2-72-80
Abstract
Current methods of the laboratory diagnostics permit to detect a large quantity of the molecular markers, typical for patients with acute myeloid leukemia. However, low frequency of some aberrations does not not to determine their prognostic value. Thus, the necessity of the selection of the most frequent and prognostically significant molecular markers specifies the actuality of the present research. We analyzed the incidence and prognostic relevance of NRAS, CKIT, FLT3 and NPM1 mutations in 200 AML patients. Cytogenetic and molecular-genetic analysis was carried out by GTG-method, PCR and sequencing. We found out, that mutations in CKIT, FLT3 and NPM1 significantly influence on the prognosis, thereby the algorithm of genetic diagnostics of AML patients was suggested. We underlined the importance of the detection of simultaneous mutations in genes with different functionality.
About the Authors
E. V. PetrovaRussian Federation
Petrova Ekaterina V., BD, PhD, research associate of laboratory of molecular genetics
191024, St.Petersburg
I. S. Martynkevich
Russian Federation
191024, St.Petersburg
L. B. Polushkina
Russian Federation
191024, St.Petersburg
L. S. Martynenko
Russian Federation
191024, St.Petersburg
M. P. Ivanova
Russian Federation
191024, St.Petersburg
N. Yu. Tsybakova
Russian Federation
St. Petersburg, 191024;
St. Petersburg, 191015
E. V. Kleina
Russian Federation
191024, St.Petersburg
E. S. Shabanova
Russian Federation
St. Petersburg, 191024;
St. Petersburg, 191015
A. V. Chechetkin
Russian Federation
191024, St.Petersburg
K. M. Abdulkadyrov
Russian Federation
191024, St.Petersburg
References
1. Grimwade D., Hills R.K., Moorman A.V., Walker H., Chatters S., Goldstone A.H., et al. Refnement of cytogenetic classifcation in acute myeloid leukemia: determination of prognostic signifcance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trial. Blood. 2010; 116-(3): 354–65.
2. Renneville A., Roumier C., Biggio V., Nibourel O., Boissel N., Fenaux P., et al. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008; 22 (5): 915–31.
3. Abu-Duhier F., Goodeve A., Wilson G., Care R., Peake I., Reilly J. Identifcation of novel FLT3 Asp835 mutations in adult acute myeloid leukaemia. Br. J. Haematol. 2001; 113 (4): 983–8.
4. Chan P.M. Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model. Protein Cell. 2011; 2 (2): 108–15. doi:10.1007/s13238-011-1020-7.
5. Georgiou G., Karali V., Zouvelou C., Kyriakou E., Dimou M., Chrisochoou S., et al. Serial determination of FLT3 mutations in myelodysplastic syndrome patients at diagnosis, follow up or acute myeloid leukaemia transformation: incidence and their prognostic signifcance. Br. J. Haematol. 2006; 134 (3): 302–6.
6. Rau R., Magoon D., Greenblatt S., Li L., Annesley C., Duffeld A., et al. NPMc+ cooperates with Flt3/ITD mutations to cause acute leukemia recapitulating human disease. Exp. Hematol. 2014; 42 (2): 101–13.
7. Fröhling S., Schlenk R., Breitruck J., Benner A., Kreitmeier S., Tobis K., et al. AML Study Group Ulm. Acute myeloid leukemia. Prognostic signifcance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002; 100 (13): 4372–80.
8. Stirewalt D., Kopecky K., Meshinchi S., Appelbaum F., Slovak M., Willman C., et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood. 2001; 97 (11): 3589–95.
9. Port M., Böttcher M., Thol F., Ganser A., Schlenk R., Wasem J., et al. Prognostic signifcance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis. Ann. Hematol. 2014; 93 (8): 1279–86.
10. Koh Y., Park J., Ahn K., Kim I., Bang S., Lee J., et al. Different clinical importance of FLT3 internal tandem duplications in AML according to FAB classifcation: possible existence of distinct leukemogenesis involving monocyte differentiation pathway. Ann. Hematol. 2009; 88 (11): 1089–97. doi: 10.1007/s00277-009-0733-7.
11. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? Hematology Am. Soc. Hematol. Educ. Program. 2013; 2013: 220–6. doi: 10.1182/asheducation-2013.1.220.
12. Meshinchi S., Appelbaum F. Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin. Cancer Res. 2009; 15 (13): 4263–9.
13. Falini B., Nicoletti I., Martelli M., Mecucci C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+AML): biologic and clinical features. Blood. 2007; 109 (3): 874–85.
14. 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 (4): 1109–20. doi: 10.1182/blood-2010-08-299990.
15. Cilloni D., Messa F., Rosso V., Arruga F., Deflippi I., Carturan S., et al. Increase sensitivity to chemotherapeutical agents and cytoplasmatic interaction between NPM leukemic mutant and NF-kappaB in AML carrying NPM1 mutations. Leukemia. 2008; 22 (6): 1234–40. doi: 10.1038/leu.2008.68.
16. Federici L., Falini B. Nucleophosmin mutations in acute myeloid leukemia: A tale of protein unfolding and mislocalization. Protein Sci. 2013; 22 (5): 545–56.
17. Johnson D.B., Smalley K.S., Sosman J.A. Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. Clin. Cancer Res. 2014; 20 (16): 4186–92.
18. Bos J.L., Verlaan-de Vries M., van der Eb A.J., Janssen J.W., Delwel R., Löwenberg B., Colly L.P. Mutations in N-Ras predominate in acute myeloid leukemia. Blood. 1987; 69: 1237–41.
19. 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): 3847–53.
20. Kiyoi H., Naoe T., Nakano Y., Yokota S., Minami S., Miyawaki S., et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood. 1999; 93 (9): 3074–80.
21. Krauth M.T., Eder C., Alpermann T., Bacher U., Nadarajah N., Kern W., 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 (7): 1449–58.
22. Care R.S., Valk P.J., Goodeve A.C., Abu-Duhier F.M., GeertsmaKleinekoort W.M., Wilson G.A., et al. Incidence and prognosis of CKIT and FLT3 mutations in core binding factor (CBF) acute myeloid leukaemias. Br. J. Haematol. 2003; 121 (5): 775–7.
23. Boissel N., Leroy H., Brethon B., Philippe N., de Botton S., Auvrignon A., 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 (6): 965–70.
24. Wang Y.Y., Zhou G.B., Yin T., Chen B., Shi J.Y., Liang W.X., et al. AML1-ETO and C-KIT mutation overexpression in t(8;21) leukemia: Implication in stepwise leukemogenesis and response to Gleevec. Proc. Natl. Acad. Sci. 2005; 102 (4): 1104–9.
25. Machado L.E., Pinho J.R., Sitnik R., Muto N.H., Velloso E.D., Petroni R.C., Campregher P.V. The detection of KIT mutations in acute myeloid leukemia. Einstein (Sao Paulo). 2012; 10 (3): 286–91.
Review
For citations:
Petrova E.V., Martynkevich I.S., Polushkina L.B., Martynenko L.S., Ivanova M.P., Tsybakova N.Yu., Kleina E.V., Shabanova E.S., Chechetkin A.V., Abdulkadyrov K.M. Clinical, hematological and molecular-genetic features of acute myeloid leukemia with mutations in FLT3, CKIT, NRAS and NPM1. Russian journal of hematology and transfusiology. 2016;61(2):72-80. (In Russ.) https://doi.org/10.18821/0234-5730-2016-61-2-72-80