Assessment of response to imatinib therapy in patients with chronic myeloid leukemia with e13a2 and e14a2 transcripts of BCR/ABL1 gene. / OTsINKA VIDPOVIDI NA TERAPIIu IMATYNIBOM U PATsIIeNTIV Z KhRONIChNOIu MIIeLOIDNOIu LEYKEMIIeIu Z E13A2 TA E14A2 TRANSKRYPTAMY GENA BCR/ABL1.

OBJECTIVE: Assess the influence of e13a2 and e14a2 transcripts of BCR/ABL1 gene on the efficiency of imatinib ther apy in patients with chronic myeloid leukemia. MATERIALS AND METHODS: We examined 508 patients with the chronic phase of chronic myeloid leukemia without radi ation in anamnesis as well as 13 patients with the similar diagnosis and with confirmed presence of radiation expo sure due to the Chornobyl Nuclear Power Plant accident. RESULTS: No significant differences in hematologic parameters, rate of additional chromosomal aberrations and f vari ant translocations were observed between patients with е13а2 and е14а2 transcript. Cumulative probability of com plete cytogenetic response did not differ in patients with е13а2 and е14а2 transcript and was 76 and 80 % respec tively (р = 0,981). Median of achieving a complete cytogenetic response was 20 months in both patient groups. Significantly more patients with e14a2 transcript compared to patients with e13a2 achieved major molecular response by 12 month of therapy (61.5 % versus 23.0 %, p = 0.016). The higher incidence of deep molecular response by 24 month of therapy was revealed in this group (38.7 % versus 6.25 %, p = 0.018). The overall survival and pro gression free survival rates were not statistically different between two groups with different transcripts. However, the rate of event free survival was statistically lower for the patients with e13a2 transcript compared to the ones with e14a2 transcript (51 % versus 62.0 %, p = 0.039). The number of primary resistant patients was 40 % regardless of the transcript expressed. A significant prevalence in incidence either of lost complete cytogenetic response or fail ure of the major molecular response was shown in patients with e13a2 transcript compared to patients with e14a2 transcripts (43.5 % versus 24.8 %, p = 0.015). CONCLUSION: Imatinib therapy is more effective for CML patients with e14a2 transcript compared to patients with e13a2 transcript expression. The transcript e13a2can be viewed as a adverse prognostic factor for imatinib therapy of chronic myeloid leukemia.

The efficiency of tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia exposed to ionizing radiation due to the Chornobyl nuclear power plant accident. / Efektyvnist'' terapii' ingibitoramy tyrozynkinaz pacijentiv z hronichnoju mijeloi'dnoju lejkemijeju, jaki zaznaly vplyvu ionizujuchogo vyprominjuvannja vnaslidok avarii' na Chornobyl''s''kij AES.

Objective. To study the efficiency of tyrosine kinase inhibitors (TKI) therapy in patients with chronic myeloid leukemia (CML) exposed to ionizing radiation due to the Chornobyl NPP accident, based on the data of cytogenetic and molecular monitoring. Material and methods. 29 CML patients with confirmed radiation exposure due to Chornobyl NPP accident were examined. Of these, 20 patients were treated with imatinib; 103 patients with CML without radiation history treated with TKI were a comparison group. Cytogenetic and molecular genetic disturbances before and on the different stage of TKI therapy were analysed. Results. Additional chromosomal abnormalities as well as special pattern of BCR/ABL transcripts were not revealed in CML patients exposed to ionizing radiation. Complete cytogenetic response (CCR) was shown in 50 and 48.5 % of patients from study and comparison group, respectively. Major molecular response (MMR) was achieved in 20 % of patients with radiation exposure in anamnesis and in 27.6 % of patients from comparison group. The vast majority of CCR and MMR was reached in patients with the pretreatment term up to 6 months, when imatinib was used as a first line therapy. There were less cases of primary imatinib resistance in the same group of patients. In CML patients who had a history of radiation exposure, secondary resistance developed more frequently than in the comparison group and was 25 %. Conclusion. Laboratory monitoring based on the registration of CCR and MMR demonstrated high efficiency of TKI in the CML treatment of patients, exposed due to Chornobyl accident. Extension of pretreatment term leads to the loss of TKI therapy efficiency and increases the likelihood of primary resistance. CML patients exposed to ionizing radiation develop secondary resistence more often than CML patients without radiation exposure in anamnesis.

MYC gene rearrangements detected by interphase fluorescence in situ hybridization in diffuse large B-cell lymphomas. / MYC perebudovy dyfuznyh krupnoklitynnyh B-limfom, vyjavleni za dopomogoju interfaznoi' fluorescentnoi' IN SITU gibrydyzacii'

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, including approximately 30-40% of all B-cell non-Hodgkin lymphomas (B-NHL). Chromosomal translocations are the hallmark of genetic aberrations in B-lymphoma and are often associated with a specific subtype of B-NHL. MYC gene dysregulation due to chromosomal translocations is characteristic for the most cases of Burkitt's lymphoma. Objective. The goal of this study was to improve the diagnostic accuracy of DLBCL. Identification of chromosome 8 and 14 abnormalities including the translocation of MYC gene t(8; 14)(q24; q32) in substrate cells of lymph nodes was applied using the method of tri-color interphase fluorescence in situ hybridization (I-FISH). Materials and methods. Lymph node biopsy specimens of 17 patients with diffuse large B-cell lymphoma and three patients with Burkitt's lymphoma (including one participant of liquidation of consequences of the catastrophe at the Chornobyl NPP) were studied. The age of patients ranged from 10 to 66 years old (41.3 ± 3.7 average). Biopsy specimens fixed in paraffin. I-FISH-analysis was performed using the commercial test Vysis IGH/MYC, CEP 8 tri-color, dual fusion translocation probe (Abbott Molecular, USA). Results and conclusions. MYC gene and immunoglobulin heavy chain (IGH) gene translocations were found in four out of twenty persons. Consequently the I-FISH method allows identification of of MYC and IGH gene rearrangements in tissue cells substrate of lymphoma fixed in paraffin. Using this method the molecular-cytogenetic abnormalities were found in eight of twenty patients with B-cell lymphoma providing verification of the lymphoma diagnosis, prediction of their clinical course and advance in management i.e increase the effectiveness of therapy, in refractory lymphoma cases among others.

Role of radiosensitivity and radioresistance genetic markers in hematological and cardiovascular disease in persons exposed after the Chornobyl accident.

UNLABELLED: The objective was to study the immunogenetic component contribution to the formation of post-radiation effects in the long-term period after radiation exposure at the level of the human immune response as a prognostic criterion for risk assessment of radiation-associated somatic diseases. Study object was the convalescents of acute radiation syndrome (ARS) of the first grade of severity, 88 patients with a similar radiation history but with unconfirmed ARS, 73 patients being the liquidators of the Chornobyl accident consequences (LCAC) with chronic ischemic heart disease (HIHD), 65 patients LCAC without HIHD, 120 non-exposed patients with HIHD, 256 patients with oncohematological diseases and 500 healthy people - a population control. RESULTS: Markers of risk of realization of genetic predisposition to oncohematological and cardiovascular disease in these groups were identified on the basis of study of immunological, hematological and molecular genetic disorders in relation to immunogenetic factors. CONCLUSION: These data indicate that realization of HLA-genetic predisposition to the disease is one of the radiation associated multifactorial pathology pathways, and presence of radiosensitivity markers in pheno/genotype enhances the realization risk of pathological process under irradiation.

A novel system for assigning the mode of inheritance in mitochondrial disorders using cybrids and rhodamine 6G.

When normal human cultured skin fibroblasts were treated with the fluorescent dye rhodamine 6G (R6G), there was a drastic reduction in numbers of intact mitochondria and electron transport chain enzyme activities, despite the fact that mitochondrial DNA (mtDNA) was still present in treated cells. We used this observation to develop a novel system for generating cybrids. When cultured skin fibroblast cells from a patient with the mitochondrial encephalopathy and ragged-red fibers (MERRF) syndrome harboring the A8344G mtDNA mutation and which showed a severe reduction in cytochrome c oxidase activity were treated with R6G and fused to enucleated HeLaCOT cells, the resulting cybrid clones showed recovery of cytochrome c oxidase activity, and were shown to have mtDNA derived solely from the HeLaCOT cell line. R6G has significant advantages over ethidium bromide in removing the mitochondrial elements from cultured cells, and the results reported here demonstrate that this strategy can be used to determine the origin of the genetic defect in patients with electron transport chain abnormalities.