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. 2017 Dec 1;34(4):300-306.
doi: 10.4274/tjh.2016.0489. Epub 2017 Mar 15.

FMS-Like Tyrosine Kinase 3 (FLT3) and Nucleophosmin 1 (NPM1) in Iranian Adult Acute Myeloid Leukemia Patients with Normal Karyotypes: Mutation Status and Clinical and Laboratory Characteristics

Narges Rezaei  1 , Nargess Arandi  1 , Behnaz Valibeigi  2 , Sezaneh Haghpanah  1 , Mehdi Khansalar  3 , Mani Ramzi  1
Affiliations

FMS-Like Tyrosine Kinase 3 (FLT3) and Nucleophosmin 1 (NPM1) in Iranian Adult Acute Myeloid Leukemia Patients with Normal Karyotypes: Mutation Status and Clinical and Laboratory Characteristics

Narges Rezaei et al. Turk J Haematol. .

Abstract
in English, Turkish

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.

Amaç: Bu çalışmada, İran’lı normal sitogenetikli akut miyeloid lösemi (NS-AML) hastalarında FMS-benzeri tirozin kinaz 3 (FLT3-ITD ve FLT3-TKD) ile nükleofosmin 1 (NPM1) mutasyonlarının sıklığını değerlendirdik. Mutant olmayan (yabanıl-wild-type) ve mutant olgular klinik ve laboratuvar özellikler açısından mukayese edildi. Gereç ve Yöntemler: Yetmiş yeni tanı de novo AML hastası kemoterapi uygulanması öncesinde çalısmaya dahil edildi; bunların 54’ü NS-AML idi. Mutasyonları tespit etmek için, FLT3 ve NPM1 genleri polimeraz zincir reaksiyonu ile amplifiye edildi ve bu işlemi direkt dizileme takip etti. Bulgular: NS-AML hastalarında FLT3-ITD, FLT3-TKD ve NPM1 mutasyonlarının sıklıkları sırasıyla %25,9; %5,9 ve %20,8 olarak bulunmuştur. En sık gözlenen NPM1 mutasyon tipi, tip A mutasyonuydu. FLT3-ITD mutasyonu M3 hastalarına göre M3-dışı olgularda daha sık görülmekteydi. Fransız-Amerikan-İngiliz M3 grubundaki hastalarda FLT3-TKD veya NPM1 genine ait mutasyon tespit edilmedi. NS-AML hastalarında FLT3-ITD ve NPM1 mutasyonlarının varlığı açısından anlamlı ilişki yoktu (p>0,05). FLT3-ITD, FLT3-TKD ve NPM1 mutasyon sıklığı, her ne kadar istatistiksel olarak anlamlı farklılık saptanmasa da (p>0,05), NS-AML hastalarında sitogenetik aberasyonu olan AML olgularına göre daha fazlaydı. FLT3-ITD ve NPM1 genleri açısından mutant olan ve olmayan hastalarda ortalama lökosit ve trombosit sayıları, serum hemoglobin düzeyleri ve kemik iliği blast yüzdeleri arasında anlamlı farklılık yoktu (p>0,05). Yaş ve cinsiyete göre FLT3-ITD veya NPM1 mutasyonlarının sıklıkları açısından farklılık tespit edilmedi (p>0,05). Sonuç: NPM1 hastalık sürecindeki yüksek kararlılığı nedeniyle, özellikle minimal kalıntı hastalık tespiti açısından FLT3 veya diğer bilinen genetik belirteçler ile kombine olarak hastaların izlenmesinde kullanılabilir. Anahtar Sözcükler: Akut miyeloid lösemi, Gen mutasyonu, FLT3, NPM1.

Keywords: Acute myeloid leukemia; FLT3 NPM1.; Gene mutation.

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Conflict of interest statement

Conflict of Interest: The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.

Figures

Figure 1
Figure 1. Sequencing results for FLT3-ITD and NPM1 mutation: A and B are representative of patients with wild-type and mutant FLT3-ITD gene, respectively. C and D are representative of patients with wild-type and mutant NPM1 gene, respectively. The arrows show the mutation site.
See this image and copyright information in PMC

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