REVIEWS

Pathological Metabolism of Methionine in Malignant Cells Is a Potential Target for the Antitumor Therapy

REVIEWS , , , , , ,

VS Pokrovskii1, DZh Davydov1, NV Anufrieva2, DD Zhdanov3, EM Treshchalina1, TV Demidkina2, EA Morozova2

1 NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 VA Engelhardt Institute of Molecular Biology, 32 Vavilova str., Moscow, Russian Federation, 119991

3 VN Orekhovich Institute of Biomedical Chemistry, 10 bld. 8 Pogodinskaya str., Moscow, Russian Federation, 119121

For correspondence: Vadim Sergeevich Pokrovskii, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: 8(499)324-14-09; e-mail: vadimpokrovsky@yandex.ru

For citation: Pokrovskii VS, Davydov DZh, Anufrieva NV, et al. Pathological Metabolism of Methionine in Malignant Cells Is a Potential Target for the Antitumor Therapy. Clinical oncohematology. 2017;10(3):324–32 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-324-332

ABSTRACT

This review presents the characteristics of the cellular metabolism of methionine, as well as known data on the mechanisms of the development of methionine dependence in malignant cells. The possibilities of using a non-methionine diet for the control of the tumor growth in patients with various forms of cancer are considered. The newest information about methionine-γ-lyase, an enzyme providing elimination of methionine from plasma, is grouped and summarised. Its role as a potential antitumor enzyme is disclosed. Data on methionine-γ-lyase producers, activity of this enzyme, obtained from various sources, and information on tumor models and cell cultures, showing methionine dependence are summarised.

Keywords: methionine-γ-liase, methionine, methionine dependency, cancer cells, cancer, anticancer enzymes, antitumor therapy.

Received: December 16, 2016

Accepted: March 6, 2017

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Cytogenetic and Molecular Genetic Prognostic Factors of Acute Lymphoblastic Leukemias

REVIEWS , , , ,

AV Misyurin

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Andrei Vital’evich Misyurin, PhD, 24 Kashirskoe sh., Moscow, Russian Federation, 115478; e-mail: and@genetechnology.ru

For citation: Misyurin AV. Cytogenetic and Molecular Genetic Prognostic Factors of Acute Lymphoblastic Leukemias. Clinical oncohematology. 2017;10(3):317–23 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-317-323

ABSTRACT

This review presents characteristic and reproducible chromosome rearrangements in acute lymphoblastic leukemia (ALL), which can be detected with a standard cytogenetic research (G-bands staining) or by FISH. More subtle genetic changes, inaccessible to the observation of cytogeneticists, are detected with the help of modern methods of molecular biological diagnosis. The prognostic value of cytogenetic and molecular genetic markers of ALL is shown in this article. A minimal set of clinically relevant molecular markers is presented, which it is advisable to investigate with ALL.

Keywords: acute lymphoblastic leukemia, chromosomal aberration, chimeric oncogene, gene expression, gene mutation.

Received: December 3, 2016

Accepted: March 8, 2017

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

REVIEWS , , ,

LR Tilova1, AV Savinkova1, EM Zhidkova1,2, OI Borisova1,3, TI Fetisov1,4, KA Kuzin1, OA Vlasova1, AS Antipova3, OYu Baranova3, KI Kirsanov1, GA Belitskii1, MG Yakubovskaya1, EA Lesovaya1,5

1 Institute of Carcinogenesis, NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russia, 115478

2 Moscow Technological University, 78 Vernadskogo pr-t, Moscow, Russia, 119454

3 Institute of Clinical Oncology, NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russia, 115478

4 IM Sechenov 1st Moscow Medical State University, 8 bld. 2 Trubetskaya str., Moscow, Russia, 119991

5 IP Pavlov Ryazan Medical State University, 9 Vysokovol’tnaya str., Ryazan, Russia, 390026

For correspondence: Ekaterina Andreevna Lesovaya, PhD, 24 bld. 15 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel: 8(910)471-41-28; e-mail: lesovenok@yandex.ru

For citation: Tilova LR, Savinkova AV, Zhidkova EM, et al. Molecular Genetic Abnormalities in the Pathogenesis of Hematologic Malignancies and Corresponding Changes in Cell Signaling Systems. Clinical oncohematology. 2017;10(2):235–49 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-235-249

ABSTRACT

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.

Keywords: tumors of hematopoietic and lymphoid tissues, chromosomal abnormalities, cell signaling disruption, WHO classification.

Received: September 29, 2016

Accepted: January 16, 2017

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Cytogenetic and Molecular Genetic Prognostic Factors of Acute Myeloid Leukemia

REVIEWS , , , ,

AV Misyurin

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Andrei Vital’evich Misyurin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: and@genetechnology.ru

For citation: Misyurin AV. Cytogenetic and Molecular Genetic Prognostic Factors of Acute Myeloid Leukemia. Clinical oncohematology. 2017;10(2):227–34 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-227-234

ABSTRACT

The review presents data on the diagnostic and prognostic value of cytogenetic and molecular genetic markers of acute myeloid leukemia (AML). It demonstrates that some cases, different types of AML subdivided on the basis of clinical and morphological characteristics earlier may be distinguished based on identification of specific genetic and chromosomal defects. However, some repeated chromosomal abnormalities may be detected in AML patients that may be assigned to different variants based in clinical and morphocytochemical signs. At present, it is widely accepted that changes in the karyotype are the key prognostic factors which are more important than criteria based on morphological and cytochemical signs. Therefore, the risk-adaptive therapy of AML should be chosen based on the cytogenetic test findings. The review contains a section discussing gene mutations known to date that may affect the AML treatment outcome.

Keywords: AML, chromosomal aberration, chimeric oncogene, gene expression, gene mutation.

Received: September 16, 2016

Accepted: January 3, 2017

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Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases

REVIEWS ,

AV Ponomarev

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Aleksandr Vasil’evich Ponomarev, graduate student, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: kl8546@yandex.ru

For citation: Ponomarev AV. Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases. Clinical oncohematology. 2017;10(1):29-38–хх (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-29-38

ABSTRACT

Myeloid-derived suppressor cells are immature myeloid cells with immunosuppressive properties. The review presents characteristics of myeloid-derived suppressor cells. It includes phenotype variants, mechanisms of the suppressive effect on the immune system, and tumor recruitment mechanisms of myeloid suppressors. It provides a brief description of works which studied myeloid suppressor in oncohematological diseases including multiple myeloma, lymphomas, and leukemias.

Keywords: myeloid suppressors, myeloid-derived suppressor cells, multiple myeloma, lymphomas, leukemias.

Received: September 8, 2016

Accepted: December 3, 2016

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Erythroferron: Modern Concepts of Its Role in Iron Metabolism Regulation

REVIEWS , ,

VT Sakhin1, NV Kremneva1, AV Gordienko2, OA Rukavitsyn3

1 Military Clinical Hospital No. 1586 under the Ministry of Defense of Russia, 4 Mashtakova str., Podol’sk, Moscow Oblast, Russian Federation, 142110

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 NN Burdenko Principal Military Clinical Hospital under the Ministry of Defense of Russia, 3 Gospital’naya pl., Moscow, Russian Federation, 105229

For correspondence: Valerii Timofeevich Sakhin, PhD, 4 Mashtakova str., Podol’sk, Moscow Oblast, Russian Federation, 142110; Tel: +7(916)314-31-11; e-mail: SahinVT@yandex.ru

For citation: Sakhin VT, Kremneva NV, Gordienko AV, Rukavitsyn OA. Erythroferron: Modern Concepts of Its Role in Iron Metabolism Regulation. Clinical oncohematology. 2017;10(1):25–8 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-25-28

ABSTRACT

The article presents the results of experimental and clinical studies evaluating the importance of supposed erythroid regulators of hepcidin levels and mechanism of their action. It demonstrates that the role of growth differentiation factor 15 and twisted gastrulation protein homolog 1 in regulation of hepcidin levels in humans has not been confirmed yet. The data confirming the importance of erythroferron in the pathogenesis of anemia related to blood loss, hemolysis, and hereditary anemias with ineffective erythropoiesis are presented. The studies demonstrated that erythroferron plays the greatest role in the regulation of hepcidin levels in pathological conditions and at stress and does not play a leading role in erythropoiesis under normal conditions. Erythroferron suppresses the hepcidin synthesis by affecting the liver cells directly through an unknown receptor cellular pathway.

Keywords: anemia of chronic disease, hepcidin, erythroferron.

Received: September 14, 2016

Accepted: November 13, 2016

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Primary Mediastinal (Thymic) Large B-Cell Lymphoma

REVIEWS , , , , , ,

GS Tumyan, IZ Zavodnova, MYu Kichigina, EG Medvedovskaya

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Gayane Sergeevna Tumyan, DSci, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel: +7(499)324-98-29; e-mail: gaytum@mail.ru

For citation: Tumyan GS, Zavodnova IZ, Kichigina MYu, Medvedovskaya EG. Primary Mediastinal (Thymic) Large B-Cell Lymphoma. Clinical oncohematology. 2017;10(1):13–24 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-13-24

ABSTRACT

Primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is one of the primary extranodal tumors and originates from thymic medulla B cells. The disease is more common in young women and declares itself by mainly locally advanced growth within the anterior upper mediastinum with frequent involvement of chest organs. PMBCL has specific morphological, immunological, and genetic characteristics that permit to differentiate it from other similar diseases: diffuse large В-cell lymphoma, nodular sclerosis Hodgkin’s lymphoma, and mediastinal gray zone lymphoma. Immunochemotherapy with subsequent irradiation of the residual mediastinal tumor is the standard treatment of PMBCL. No benefits of one drug therapy over another have been demonstrated to date in controlled studies. Application of new imaging techniques (PET/CT) may result in withdrawal of the radiotherapy in some PMBCL patients without impairment of delayed survival rates.

Keywords: primary mediastinal (thymic) large B-cell lymphoma, primary extranodal lymphomas, diagnosis, pathogenesis, morphological, immunological/genetic characteristics, treatment.

Received: August 22, 2016

Accepted: December 17, 2016

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Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma

REVIEWS , , ,

SV Gritsaev, AA Kuzyaeva, SS Bessmel’tsev

Russian Scientific Research Institute of Hematology and Transfusiology under the Federal Medico-Biological Agency, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

For correspondence: Sergei Vasil’evich Gritsaev, DSci, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel: +7(812)717-58-57; e-mail: gritsaevsv@mail.ru

For citation: Gritsaev SV, Kuzyaeva AA, Bessmel’tsev SS. Certain Aspects of Autologous Hematopoietic Stem Cell Transplantation in Patients with Multiple Myeloma. Clinical oncohematology. 2017;10(1):7–12 (In Russ).

DOI: 10.21320/2500-2139-2017-10-1-7-12

ABSTRACT

The review dwells on certain problems of mobilization and conditioning regimens, as well as autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with multiple myeloma. The aim of the review is to determine new approaches to improve the effectiveness of the auto-HSCT.

Keywords: multiple myeloma, autologous hematopoietic stem cell transplantation, mobilization regimen, conditioning regimen.

Received: July 13, 2016

Accepted: November 12, 2016

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Hypomethylating Agents in Oncohematology

REVIEWS , , , ,

AD Shirin, OYu Baranova

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Anton Dmitrievich Shirin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-28-24; e-mail: shirin-anton@mail.ru

For citation: Shirin AD, Baranova OYu. Hypomethylating Agents in Oncohematology. Clinical oncohematology. 2016;9(4):369–82 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-369-382

ABSTRACT

The review describes epigenetic processes, including methylation of nuclear and mitochondrial DNA, as well as RNA. It dwells on mechanisms of demethylation and corresponding medicinal products. It presents detailed information on results of numerous large randomized studies intended to evaluate hypomethylating agents (azanucleosides). Special attention is paid to outcomes of azanucleoside therapy in patients with acute myeloid leukemias. The article describes several prognostic systems and treatment algorithms for myelodysplastic syndromes. Two azanucleosides have been approved in Russia to date: azacitidine (for SQ administration) and decitabine (for IV administration). International authors analyze the experience in oral and subcutaneous administration of decitabine. However, the problem of off-label use of hypomethylating agents is still open. The review gives a brief description of ongoing clinical trials with azanucleosides.

Keywords: epigenetics, acute myeloid leukemias, myelodysplastic syndromes, azacitidine, decitabine, hypomethylating agents, azanucleosides.

Received: May 10, 2016

Accepted: May 20, 2016

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Application of Modern Genome Technologies in Treatment of Lymphomas

REVIEWS , , ,

MV Nemtsova1, MV Maiorova2

1 Russian Medical Academy of Postgraduate Education, 2/1 Barrikadnaya str., Moscow, Russian Federation, 125993

2 PA Hertzen Moscow Oncology Research Institute, 3 2-y Botkinskii pr-d, Moscow, Russian Federation, 125284

For correspondence: Marina Vyacheslavovna Nemtsova, DSci, Professor, 2/1 Barrikadnaya str., Moscow, Russian Federation, 125993; Tel: +7(499)252-21-04; e-mail: nemtsova_m_v@mail.ru

For citation: Nemtsova MV, Maiorova MV. Application of Modern Genome Technologies in Treatment of Lymphomas. Clinical oncohematology. 2016;9(3):265-70 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-265-270

ABSTRACT

Modern achievements in genomics and cancer biology have provided an unprecedented body of knowledge regarding the molecular pathogenesis of lymphoma. Genome-wide association studies and modern computer technologies demonstrated that various histological and immunomorphological subtypes of lymphomas differ at the molecular level, and result from various oncogenic mechanisms. It is clear that the variability of clinical symptoms presented by patients with lymphomas is based on the heterogeneity of tumor cells and features of the molecular pathogenesis. Based on data obtained, strategies for the development of new drugs for treatment of lymphoma have been proposed, including identification of the molecular pathogenesis, assessment of the significance of each stage for the development of tumors and synthesis of a drug with a targeted effect. As a result, several new classes of molecular targeted agents for treatment of lymphomas have been proposed and are being tested in clinical trials. In the modern era of personalized medicine, correct targeted therapy for each type of lymphoma characterized by a unique molecular mechanism of tumor formation is a major challenge in lymphoma treatment.

Keywords: lymphoma, genes expression profile, microRNA, signaling pathways, NF-kB.

Received: February 13, 2016

Accepted: March 14, 2016

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