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ИННОВАЦИОННЫЕ ТЕХНОЛОГИИ В ПЕДИАТРИИ И ДЕТСКОЙ ХИРУРГИИ
sis and were identified in our laboratory between the years 2000 and 2015. Of 458 CML cases 24 patients (5.2%) exhibited vPhs with overall 29 different breakpoints; the most frequent repeated breakpoint was 16p11.2, and chromosome 12 was the most frequently involved in our vPhs cases. The majority of the cases were simple translocations (75%) and 25% of these cases were complex translocations. Deletions in 9q34 on the der(9) were observed in four of the 22 vPh cases (18.1%), which was not associated with a lower rate of ABL1 or BCR deletion status compared to the average of ~40% reported in the literature. Mainly vPhs cases revealed a one-step mechanism of translocation formation (22 of 24 vPhs cases, 91.6%), despite one case exhibiting most likely a two-step mechanism, and only one case was due to a complex multi-step mechanism.
INFLUENCE OF GLUTATHIONE S-TRANSFERASE (GSTT1 AND GSTM1) GENE POLYMORPHISM ON IMATINIB FAILURE IN CHRONIC MYELOID LEUKEMIA PATIENTS
Al Achkar W.1, Moassass F.1, Aroutiounian R.2, Harutyunyan T.2, Liehr T.3, Wafa A.1
'Human Genetics Division, Department of Molecular Biology and Biotechnology, Atomic Energy Commission of Syria, Damascus, Syria 2Department of Genetics and Cytology, Yerevan State University, Yerevan, Armenia 3Institute of Human Genetics, Jena University Hospital, Jena, Germany
Chronic myeloid leukemia (CML) is genetically characterized by the occurrence of a reciprocal translocation t(9;22)(q34;q11), resulting in a BCR/ABL1 gene fusion on the derivative chromosome 22, i.e. the Philadelphia (Ph) chromosome. Imatinib (IM) is a chemically designed drug which blocks BCR/ABL1 tyrosine kinase activity and is successfully used in CML patients. However, some CML patients fail to reach adequate hematologic, cytogenetic and molecular responses or develop resistance to IM treatment. It has been reported that mutations or amplification of BCR-ABL1 kinase domain or variation in the bioavailability of IM may be linked to inherited genetic differences of enzymes involved in IM metabolism and thus those could explain interindividual differences in treatment outcome. Glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes known to be involved in the detoxification of carcinogens and anticancer drugs. Individual genetic variation expressed as inherited polymorphisms of GSTT1 and GSTT1 may lead to complete loss of enzyme activity; this could expose subjects to develop cancer and/or to induce drug resistance. Here we assessed the role of such GSTs in relation to IM treatment outcome in 96 Syrian CML patients. Interestingly, patients carrying GSTT1 and GSTT1 deletions did not suffer from failed IM treatment more frequently than those having the genes not-deleted (P = 0.271). However, patients with GSTT1 and/or GSTT1 deletion developed more likely only minimal cytogenetic response and IM treatment was more likely to fail (P = 0.001). Also, the
same effect was present in patients with deletion of both copies of GSTT1 (P = 0.009). On the other hand However, 5/8patients with minimal cytogenetic response developed clonal cytogenetic evolution; four of those who had ho-mozygous deletion of GSTT1. GSTT1 gene presence or absence had no influence on the cytogenetic responses in the studied CML patients (P = 0.279). Cytogenetic response and GSTT1 and/or GSTT1 gene loss are therefore important determinants of IM failure in CML. Screening for GSTT1 and GSTT1 gene deletions at time of diagnosis may identify patients who may be better treated by an alternative therapy.
BIRC3 ALTERATIONS IN CHRONIC AND B-CELL ACUTE LYMPHOCYTIC LEUKEMIA PATIENTS
Alhourani E.1, Othman Moneeb A.K.2, Melo J.B.2-3, Carreira I.M.2-3, Grygalewicz B.4, Vujic D.5-6, Zecevic Z.6, Joksic G.7, Glaser A.1, Pohle B.1, Schlie C.1, Hauke S.8, Liehr T.1
•Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Jena, Germany 2Laboratory of Cytogenetics and Genomics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal 3CIMAGO, Centro de Investiga gaoem, Meio Ambiente, Genéticae Oncobiologia, Coimbra, Portugal "Cytogenetic Laboratory, Maria Sklodowska-Curie Memorial Cancer Centre and Institute, Warsaw, Poland 5University of Belgrade Faculty of Medicine, Belgarde, Serbia
6Mother and Child Health Care Institution of Serbia "Dr. Vukan Cupic", Belgrade, Serbia 7Vinca Institute of Nuclear Sciences, Belgrade, Serbia 8ZytoVision GmbH, Bremerhaven, Germany
Deletions within the long arm of chromosome 11, subbands q22 to q23 are considered to be among the most common chromosomal aberrations in chronic lympho-cytic leukemia (CLL). They are associated with a poor outcome. Besides the ATM also the BIRC3 gene is located in this region. The latter is a negative regulator of the non-canonical NF-kB protein. Moreover, BIRC3 disruption is known to be restricted to CLL fludarabine refractory patients. The aim of this study was to determine the frequency of copy number changes of BIRC3 gene and to align with two known negative predictors of CLL-outcome, i.e. ATM and TP53 deletions. Besides, the yet suggested specificity of BIRC3 alterations to CLL patients (117 patients were included in this study) BIRC3 copy numbers were also studied in 45 B-cell acute lymphocytic leukemia (B-ALL) patients. A commercially available multiplex ligation dependent probe amplification probe set was applied, which includes 4 probes for detection of TP53, and 4 others for ATM gene region. In-terphase-directed fluorescence in situ hybridization was done applying commercially available probes for BIRC3, ATM, and TP53. High resolution array-comparative genomic hybridization was applied for selected cases. Genetic abnormalities of BIRC3 were detected in 23/117 (~20%) CLL and also in 2/45 (~4%) B-ALL cases. Over-
РОССИЙСКИЙ ВЕСТНИКПЕРИНАТОЛОГИИ И ПЕДИАТРИИ, 4, 2015
