Molecular Genetic Abnormalities in the Pathogenesis of Hematologic Malignancies and Corresponding Changes in Cell Signaling Systems

Hematological disorders include a wide spectrum of malignancies of hematopoietic and lymphoid tissues. The genetic changes underlying the pathogenesis of the diseases are specific for each disease. High incidence of chromosomal aberrations (deletion, translocation, insertion) is one of the principal characteristics of oncohematological diseases. In addition, mutations in individual genes or blocking of normal regulation of gene functioning in relation to epigenetic events can occur. Progression of oncohematological diseases could be a result of accumulation of different genetic abnormalities. Modern classification of malignancies of hematopoietic and lymphoid tissues is based on the analysis of clinical data, morphological and functional characteristics of tumor cells and identification of specific cytogenetic and molecular-genetic changes. A large number of genetic abnormalities specific for certain types of hematological malignancies has been discovered to date. It allows to optimize the treatment strategy, as well as to design, test and introduce to the clinical practice a number of targeted drugs (inhibitors of chimeric proteins formed as a result of translocations and triggering the malignant cell transformation). Drugs based on monoclonal antibodies (Rituximab, Alemtuzumab, etc.) or low molecular weight compounds (Imatinib, Bortezomib, Carfilzomib) form this group of medications. The knowledge about not only specific gene abnormalities but also about the corresponding changes in cell efferent signaling pathways could be of great interest for the development of new targeted molecules or the repurposing of known chemotherapeutic agents. The present review compares genetic aberrations in diseases listed in the 2008 WHO classification (amended in 2016) of hematopoietic and lymphoid tissue malignancies and main changes in cell signaling pathways associated with malignant transformation of hematopoietic cells

NK-Cell Lymphoblastic Leukemia/Lymphoma (Literature Review and Authors’ Experience)

Aim. To investigate clinical and laboratory features of NK-cell lymphoblastic leukemia/lymphoma (NK-LL). Methods. Of 161 patients treated in the Department of Chemotherapy of Hemoblastoses of the N.N. Blokhin Russian Cancer Research Center from 2000 to 2014, NK-LL was diagnosed in 1 patient (0.6 %). In the Laboratory of Hematopoietic Immunology of the N.N. Blokhin Russian Cancer Research Center, NK-LL was diagnosed in 3 more patients referred from other healthcare institutions over the same period of time. The disease was diagnosed in accordance with the 2008 WHO criteria. Therefore, the NK-LL group consisted of 4 patients (3 men and 1 woman) aged 29, 40, 59, and 82. Results. All patients had total bone marrow blast metaplasia (> 70 %) and extramedullary lesions in the form of generalized lymphadenopathy, hepatosplenomegaly, lesions of skin, tonsils, mediastinum, and CNS in the form of neuroleukemia. Cytochemical response in blast cells to myeloperoxidase, lipids, and nonspecific esterase was negative. In all patients, expression of CD56 antigen (69.8–99.1 %) and T-associated CD7 antigen (66.2–92.0 %) were found on blast cells. There was no expression of myeloid, T- and B-lymphoid antigens. In one patient, the PCR demonstrated no T-cell receptor gene chain rearrangement. The cytogenetic study was not performed in any patient. Induction therapy of NK-LL patients was carried out mainly according to treatment regimens for acute lymphoblastic leukemia. The complete remission (1 and 7 months) was achieved in 2 patients. The longest remission (20 months) was obtained using a combined regime RACOP for the treatment of a relapse. The life span after the diagnosis (beginning from the date on the initiation of therapy) was 1, 5, 17, and 29 months. Conclusion. The analysis demonstrates low efficacy of current regimens for treatment of NK-LL. The treatment success seems to depend on timely and accurate diagnosis of this complex, aggressive malignant tumor, as well as on development of new therapeutic approaches