Abstract
Objective:In this study, we evaluated the frequency of FMS-like tyrosine kinase 3 (FLT3-ITD and FLT3-TKD) and nucleophosmin (NPM1) mutations in Iranian patients with cytogenetically normal acute myeloid leukemia (CN-AML). The clinical and laboratory characteristics were compared between wild-type and mutant cases.Materials and Methods:Seventy newly diagnosed de novo AML patients were recruited at the time of diagnosis prior to chemotherapy; among them, 54 had CN-AML. For detecting mutations, the FLT3 and NPM1 genes were amplified by the polymerase chain reaction method, followed by direct sequencing.Results:Our results showed that the frequencies of FLT3-ITD, FLT3-TKD, and NPM1 mutations in CN-AML patients were 25.9%, 5.9%, and 20.8%, respectively. The most frequent NPM1 mutation type was the type A mutation. The FLT3-ITD mutation was seen more frequently in non-M3 patients compared with M3 patients. No mutation was observed in either the FLT3-TKD or the NPM1 gene in patients in the M3 French-American-British group. There was no significant association between the presence of FLT3-ITD and NPM1 mutations in CN-AML patients (p>0.05). The frequency of FLT3-ITD, FLT3-TKD, and NPM1 mutation was higher in CN-AML patients in comparison with AML patients with cytogenetic aberrations, although the differences were not statistically significant (p>0.05). There were no significant differences in mean white blood cell and platelet counts, serum hemoglobin levels, and bone marrow blast percentages between patients with wild-type and mutant FLT3-ITD and NPM1 genes (p>0.05). No difference was observed in the frequency of FLT3-ITD or NPM1 mutation regarding age or sex (p>0.05).Conclusion:Given the high stability of NPM1 during the disease course, it can be used in combination with FLT3 as well as other known genetic markers to monitor patients, especially for minimal residual disease detection.
Highlights
Acute myeloid leukemia (AML) is the most common hematologic malignancy, characterized by uncontrolled proliferation of hematopoietic stem cells resulting in abnormal accumulation of myeloblasts [1]
Our results showed that the frequencies of FMS-like tyrosine kinase 3 (FLT3)-ITD, FLT3TKD, and nucleophosmin 1 (NPM1) mutations in cytogenetically normal acute myeloid leukemia (CN-AML) patients were 25.9%, 5.9%, and 20.8%, respectively
The frequency of FLT3-ITD, FLT3-TKD, and NPM1 mutation was higher in CN-AML patients in comparison with AML patients with cytogenetic aberrations, the differences were not statistically significant (p>0.05)
Summary
Acute myeloid leukemia (AML) is the most common hematologic malignancy, characterized by uncontrolled proliferation of hematopoietic stem cells resulting in abnormal accumulation of myeloblasts [1]. Assessment of molecular abnormalities has proven to be a useful marker for risk stratification of these patients into good and poor risk subgroups [3,4,5,6] In this regard, somatic mutations of the FMS-like tyrosine kinase 3 (FLT3), nucleophosmin 1 (NPM1), and Wilms’ tumor 1 (WT1) genes have been well studied [3,7,8,9]. Two types of activating mutations have been identified in the FLT3 gene: internal tandem duplication (FLT3-ITD) of the region between exon 11 and 12 in the JM domain (occurring in 20%-25% of AML patients), and a point mutation at codon 835 of exon 17 in the TK domain (FLT3-TKD, known as D835Y, and occurring in 5%-7% of AML patients) [8,16]. Data on the correlation between FLT3-TKD and AML disease outcome are highly limited [3,4,7,17]
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