ISSN: 1300-7777 E-ISSN: 1308-5263
NPM1 Gene Type A Mutation in Bulgarian Adults with Acute Myeloid Leukemia: A Single-Institution Study [Turk J Hematol]
Turk J Hematol. 2014; 31(1): 40-48 | DOI: 10.4274/Tjh.2013.0023  

NPM1 Gene Type A Mutation in Bulgarian Adults with Acute Myeloid Leukemia: A Single-Institution Study

Gueorgui Balatzenko1, Branimir Spassov2, Nikolay Stoyanov3, Penka Ganeva2, Tihomit Dikov4, Spiro Konstantinov5, Vasil Hrischev6, Malina Romanova7, Stavri Toshkov7, Margarita Guenova3
1National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Cytogenetics And Molecular Biology, / Center Of Excellence For Translational Research İn Hematology, Sofia, Bulgaria
2Center Of Excellence For Translational Research In Hematology, / National Specialized Hospital For Active Treatment Of Hematological Diseases, Hematology Clinic, Sofia, Bulgaria
3Center Of Excellence For Translational Research In Hematology, / National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Hematopathology And Immunology, Sofia, Bulgaria
4National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Hematopathology And Immunology, Sofia, Bulgaria
5National Specialized Hospital For Active Treatment Of Hematological Diseases, Hematology Clinic, / Medical University Of Sofia, Faculty Of Pharmacy, Department Of Pharmacology, Toxicology And Pharmacotherapy, Sofia, Bulgaria
6National Specialized Hospital For Active Treatment Of Hematological Diseases, Hematology Clinic, Sofia, Bulgaria
7National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Cytogenetics And Molecular Biology, Sofia, Bulgaria

OBJECTIVE: Mutations of the nucleophosmin (NPM1) gene are considered as the most frequent acute myeloid leukemia (AML)- associated genetic lesion, reported with various incidences in different studies, and type A (NPM1-A) is the most frequent type. However, since most series in the literature report on the features of all patients regardless of the type of mutation, NPM1-A(+) cases have not been well characterized yet. Therefore, we evaluated the prevalence of NPM1-A in Bulgarian AML patients and searched for an association with clinical and laboratory features.
METHODS: One hundred and four adults (51 men, 53 women) were included in the study. NPM1-A status was determined using allele-specific reverse-transcription polymerase chain reaction with co-amplification of NPM1-A and β-actin and real-time quantitative TaqMan-based polymerase chain reaction. Patients received conventional induction chemotherapy and were followed for 13.2±16.4 months.
RESULTS: NPM1-A was detected in 26 (24.8%) patients. NPM1-A mutation was detected in all AML categories, including in one patient with RUNX1-RUNX1T1. There were no differences associated with the NPM1-A status with respect to age, sex, hemoglobin, platelet counts, percentage of bone marrow blasts, splenomegaly, complete remission rates, and overall survival. NPM1-A(+) patients, compared to NPM1-A(-) patients, were characterized by higher leukocyte counts [(75.4±81.9)x109/L vs. (42.5±65.9)x109/L; p=0.049], higher frequency of normal karyotype [14/18 (77.8%) vs. 26/62 (41.9%); p=0.014], higher frequency of FLT3-ITD [11/26 (42.3%) vs. 8/77 (10.4%); p=0.001], and lower incidence of CD34(+) [6/21 (28.8%) vs. 28/45 (62.2%); p=0.017]. Within the FLT3-ITD(-) group, the median overall survival of NPM1-A(-) patients was 14 months, while NPM1-A(+) patients did not reach the median (p=0.10).
CONCLUSION: The prevalence of NPM1-A mutation in adult Bulgarian AML patients was similar to that reported in other studies. NPM1-A(+) patients were characterized by higher leukocyte counts, higher frequency of normal karyotypes and FLT3- ITD, and lower incidence of CD34(+), supporting the idea that the specific features of type A mutations might contribute to the general clinical and laboratory profile of NPM1(+) AML patients.

Keywords: Acute myeloid leukemia, NPM1 gene type A mutation, FLT3-ITD, allele-specific polymerase chain reaction


Akut Miyeloid Lösemi Olan Erişkin Bulgar Hastalarda NPM1 Geni Tip A Mutasyonu: Tek Merkez Çalışması

Gueorgui Balatzenko1, Branimir Spassov2, Nikolay Stoyanov3, Penka Ganeva2, Tihomit Dikov4, Spiro Konstantinov5, Vasil Hrischev6, Malina Romanova7, Stavri Toshkov7, Margarita Guenova3
1National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Cytogenetics And Molecular Biology, / Center Of Excellence For Translational Research İn Hematology, Sofia, Bulgaria
2Center Of Excellence For Translational Research In Hematology, / National Specialized Hospital For Active Treatment Of Hematological Diseases, Hematology Clinic, Sofia, Bulgaria
3Center Of Excellence For Translational Research In Hematology, / National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Hematopathology And Immunology, Sofia, Bulgaria
4National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Hematopathology And Immunology, Sofia, Bulgaria
5National Specialized Hospital For Active Treatment Of Hematological Diseases, Hematology Clinic, / Medical University Of Sofia, Faculty Of Pharmacy, Department Of Pharmacology, Toxicology And Pharmacotherapy, Sofia, Bulgaria
6National Specialized Hospital For Active Treatment Of Hematological Diseases, Hematology Clinic, Sofia, Bulgaria
7National Specialized Hospital For Active Treatment Of Hematological Diseases, Laboratory Of Cytogenetics And Molecular Biology, Sofia, Bulgaria

AMAÇ: Nukleofosmin (NPM1) genine ait mutasyonlar değişik çalışmalarda farklı insidanslar bildirilmekle birlikte, akut miyeloid lösemi (AML)-ilişkili genetik bozuklukların en sık görülenidir ve bunlar arasında tip A (NPM1-A) en sık rastlanan tipidir. Ancak literatürdeki serilerin çoğu mutasyon tipinden bağımsız olarak tüm hastaların özelliklerini sunmakta olup, NPM1-A(+) olgular bundan önce ayrıntılı olarak tanımlanmamıştır. Bu yüzden, Bulgar AML hastalarında NPM1-A prevalansı değerlendirilmiş, klinik ve laboratuvar özellikler ile ilişkileri araştırılmıştır.
YÖNTEMLER: Çalışmaya yüz dört hasta (51 erkek, 53 kadın) dahil edilmiştir. NPM1-A durumu allel-özgül polimeraz zincir reaksiyonu ile NPM1-A ve b-aktinin birlikte amplifikasyonu ve gerçek-zamanlı TaqMan-bazlı polimeraz zincir reaksiyonu ile belirlenmiştir. Hastalar konvansiyonel indüksiyon kemoterapisi almış ve 13,2±16,4 ay takip edilmişlerdir.
BULGULAR: NPM1-A 26 hastada (%24,8) tespit edildi. NPM1-A mutasyonu, RUNX1-RUNX1T1 taşıyan bir hastayı da içeren tüm AML kategorilerinde gösterilmiştir. Yaş, cinsiyet, hemoglobin, trombosit sayısı, kemik iliğindeki blast yüzdesi, splenomegali, tam remisyon oranları ve genel sağkalım ile NPM1-A durumu ile ilişkili farklılık saptanmadı. NPM1-A(+) hastalar, NPM1-A(-) hastalar ile karşılaştırıldıklarında daha yüksek lökosit sayısına [(75,4±81,9)x109/L vs. (42,5±65,9)x109/L; p=0,049], daha sık normal karyotipe [14/18 (%77,8) vs. 26/62 (%41,9); p=0,014], daha sık FLT3-ITD’ye [11/26 (%42,3) vs. 8/77 (%10,4); p=0,001] sahipti ve daha seyrek CD34 (+) [6/21 (%28,8) vs. 28/45 (%62,2); p=0,017] idi. FLT3-ITD(-) grup içinde, NPM1-A(-) hastaların ortanca genel sağkalımı 14 aydı, ancak NPM1-A(+) hastalar ortancaya ulaşmadı (p=0,10).
SONUÇ: Erişkin Bulgar hastalarda NPM1-A mutasyonunun prevalansı diğer çalışmalarda bildirilenlerle benzer bulundu. NPM1-A(+) hastalar, tip A mutasyonların spesifik özelliklerinin NPM1(+) AML hastaların genel klinik ve laboratuvar profiline katkıda bulunabileceği fikrini destekler nitelikte yüksek lökosit sayısı, daha sık normal karyotip ve FLT3-ITD ile daha seyrek CD34(+) sıklığı ile karakterizeydi.

Anahtar Kelimeler: Akut miyeloid lösemi, NPM1 geni tip A mutasyonu, FLT3-ITD, allel-özgül polimeraz zincir reaksiyonu


Gueorgui Balatzenko, Branimir Spassov, Nikolay Stoyanov, Penka Ganeva, Tihomit Dikov, Spiro Konstantinov, Vasil Hrischev, Malina Romanova, Stavri Toshkov, Margarita Guenova. NPM1 Gene Type A Mutation in Bulgarian Adults with Acute Myeloid Leukemia: A Single-Institution Study. Turk J Hematol. 2014; 31(1): 40-48

Corresponding Author: Gueorgui Balatzenko, Türkiye


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