FLT3 and NPM1 gene mutations in patients with acute myeloid leukemias and the impact of FLT3-ITD mutations on the survival of patients with a normal karyotype
- Authors: Martynkevich I.S.1, Gritsaev S.V.1, Moskalenko M.V.1, Ivanova M.P.1, Aksenova V.Y.1, Tiranova S.A.1, Abdulkadyrov K.M.1, Martynkevich IS2, Gritsayev SV2, Moskalenko MV2, Ivanova MP2, Aksenova VY.2, Tiranova SA2, Abdulkadyrov KM2
-
Affiliations:
- Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
- Russian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
- Issue: Vol 82, No 12 (2010)
- Pages: 33-39
- Section: Editorial
- URL: https://journals.rcsi.science/0040-3660/article/view/30741
- ID: 30741
Cite item
Full Text
Abstract
Materials and methods. The nucleus-containing cells of bone marrow and blood were studied in 43 patients with AML. Polymerase chain reaction analysis of total genomic DNA was applied.
Results. Mutations of FLT3-ITD, FLT3-TDK, and the NPM1 gene were found in 16 (37.2%) patients. A total of 19 mutations were revealed. There were 8 mutations of FLT3-ITD, 5 of FLT3-TKD, and 6 in the NPM1 gene. Single damages to genes were detected in 13 patients: FLT3-ITD in 6 (13.9%), FLT3-TKD in 4 (9.3%), and NPM1 in 3 (7%). Three (7%) patients exhibited 2 mutations simultaneously: in the NPM1 and FLT3-ITD in 2 (4.7%) and in the NPM1 gene and FLT3-TKD in 1 (2.3%). In AML patients with a normal karyotype and the FLT3-ITD-/NPM1- and FLT3-ITD+/ NPM1- genotypes, median overall survival was 17.3 versus 8 months (p = 0.069); and event-free survival (EFS) was 11 versus 5 months (p = 0.026). Univariate analysis established the negative impact of FLT3-ITD mutation on EFS.
Conclusion. The findings allow AML patients with a normal karyotype and the FLT3-ITD-/NPM1- genotypes to be identified as a poor prognosis group.
Keywords
About the authors
Irina Stepanovna Martynkevich
Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
Email: genetics.spb@mail.ru
канд. биол. наук, вед. науч. сотр., ФГУ РНИИГТ ФМБА, тел.: 8-812-717-44-66; Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
Sergey Vasil'evich Gritsaev
Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентствад-р мед. наук, вед. науч. сотр; Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
Mikhail Viktorovich Moskalenko
Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентствамл. науч. сотр; Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
Marina Petrovna Ivanova
Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентстванауч. сотр; Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
Vasilisa Yur'evna Aksenova
Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентствамл. науч. сотр; Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
Sof'ya Aleksandrovna Tiranova
Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентстваврач клинической лабораторной диагностики, клинико-диагностическая лаб; Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
Kudrat Mugutdinovich Abdulkadyrov
Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентствад-р мед. наук, проф., рук. клинического отд-ния "Гематология"; Федеральное государственное учреждение Российский научно-исследовательский институт гематологии и трансфузиологии Федерального медико-биологического агентства
I S Martynkevich
Russian Research Institute of Hematology and Transfusion, Federal Biomedical AgencyRussian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
S V Gritsayev
Russian Research Institute of Hematology and Transfusion, Federal Biomedical AgencyRussian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
M V Moskalenko
Russian Research Institute of Hematology and Transfusion, Federal Biomedical AgencyRussian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
M P Ivanova
Russian Research Institute of Hematology and Transfusion, Federal Biomedical AgencyRussian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
V Yu Aksenova
Russian Research Institute of Hematology and Transfusion, Federal Biomedical AgencyRussian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
S A Tiranova
Russian Research Institute of Hematology and Transfusion, Federal Biomedical AgencyRussian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
K M Abdulkadyrov
Russian Research Institute of Hematology and Transfusion, Federal Biomedical AgencyRussian Research Institute of Hematology and Transfusion, Federal Biomedical Agency
References
- Dohner H. Implication of the molecular characterization of acute myeloid leukemia. In: Hematology (American Society Hematol. Education. Program). Pavia; 2007. 412-419.
- Mrozek K., Marcucci G., Paschka P. et al. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood 2007; 109(2): 431-448.
- Грицаев С. В., Мартынкевич И. С., Иванова М. П. и др. Целесообразность изучения FLT3, RAS и WT1 онкогенов у больных острым миелобластным лейкозом и миелодиспластическим лейкозом. Вестн. гематол. 2007; 3: 27-45.
- Kottaridis P. D., Gale R. E., Frew M. E. et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia 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. Blood 2001; 98(6): 1752-1759.
- Schnittger S., Schoch C., Dugas M. et al. Analysis of FLT3 length mutation in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100(1): 59-66.
- 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.
- Thiede C., Koch S., Creutzig E. et al. Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia. Blood 2006; 107(10): 4011-4020.
- Falini B., Meccici C., Tiacci E. et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with normal karyotype. N. Engl. J. Med. 2005; 352(3): 254-266.
- Bacher U., Kern W., Schnittger S. et al. Population-based age-specific incidences of cytogenetic subgroups of acute myeloid leukemia. Haematologica 2005; 90(11): 1502-1510.
- Schlenk R., Krauter J., Frohling S. et al. Postremission therapy with an allogeneic transplantation from an HLA-matched family donor seems to overcome the negative prognostic impact of FLT3-ITD in younger patients with acute myeloid leukemia exhibiting a normal karyotype. Blood 2005; 106(11): Abstr. 662a.
- 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.
- Vardiman J. W., Thiele J., Arber D. A. et al. The 2008 revision of the World Health Organization classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114(5): 937-951.
- Slovak M. L., Kopecky K. J., Cassileth P. A. et al. Karyotypic analysis predicts outcome of permission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Croup study. B1ood 2000; 96(13): 4075-4083.
- Kiyoi H., Naoe T., Nakano Yasuyuki et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93(9): 3074-3080.
- Blum W. Post-remission therapy in acute myeloid leukemia: what should I do now? Haematologica 2008; 93(6): 801-805.
- Kottaridis P. D., Gale R. E., Langabeer S. E. et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 2002; 100(7): 2393-2398.
- Schnittger S., Kern W., Tschulik C. et al. Minimal residual disease levels assessed by NPM1 mutation-specific PQ-PCR provide important information in AML. Blood 2009; 114(11): 2220-2231.
- Boissel N., Cayuela J. M., Preudhomme C. et al. Prognostic significance of FLT3 internal tandem repeat in patients with de novo acute myeloid leukemia treated with reinforced courses of chemotherapy. Leukemia 2002; 16(9): 1699-1704.
- Rausei-Mills V., Chang K. L., Gaal K. K. et al. Aberrant expression of CD7 in myeloblasts is highly associated with de novo acute myeloid leukemias with FLT/ITD mutation. Am. J. Clin. Pathol. 2008; 129(4): 624-629.
- Rombouts E. J. C., Pavic B., Lowenberg B., Ploemacher R. E. Relation between CXCR-4 expression, Flt3 mutations, and unfavorable prognosis of adult acute myeloid leukemia. Blood 2004; 104(2): 550-557.
- Kayser S., Schlenk R. F., Londono M. C. et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 2009; 114(12): 2386-2392.
- Hess C. J., Feller N., Denkers F. et al. Correlation of minimal residual disease cell frequency with molecular genotype in patients with acute myeloid leukemia. Haematologica 2009; 94(1): 46-53.
- Lowenberg B., Ossenkoppele G. J., van Putten W. et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N. Engl. J. Med. 2009; 361(13): 1235-1248.
- Frohllng S., Schlenk R. F., Breitruck J. et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 2002; 100(13): 4372-4380.
- Santamaria C. M., Chillon M. C., Garcia-Sanz R. et al. Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia. Blood 2009; 114(1): 148-152.
![](/img/style/loading.gif)