Long-term exposure to low doses of ionizing radiation and COVID-19 pandemic: oncohematological aspects.

For more than 35 years after Chornobyl catastrophe, about 5 million people in Ukraine, Republic of Belarus and Russian Federation inhabit the territories that are residually contaminated with long-lived radionuclides such as 137Cs, 90Sr. The previous studies of the Reference Laboratory operating at RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology allowed specifying the effects of the protracted low dose irradiation on the state of the hematopoietic and lymphoid tissues resulting in the increased proportion of the B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma and acute myeloid leukemia among the patients referred from the contaminated areas of Ukraine. Since the beginning of 2020, these effects of radiation were superimposed by the factors associated with COVID-19 pandemic. SARS-CoV-2 infection is associated with the significant impact on hematopoiesis and immune system. Particular attention should be given to the role of such combined burden in the development of the immunodeficiency-associated lymphoid neoplasms. The extensive studies of the combined effects of low dose irradiation and COVID-19 within the large affected populations could be made a priority in future endeavors of epidemiologists and oncohematologists.

Immunodeficiency-associated lymphoproliferative disorders and lymphoid neoplasms in post-COVID-19 pandemic era.

The 2017 revision of WHO Classification of tumors of hematopoietic and lymphoid tissues contains separate chapters on the immunodeficiency-associated lymphoproliferative disorders. In this mini-review, the brief description of pathological, immunophenotypical and clinical features of lymphoid neoplasms associated with primary immune disorders, HIV infection, those arising in post-transplant setting and other lymphoproliferative disorders (excluding those induced by radiation) is given. The heterogeneous spectrum of these lymphoid malignancies is specified by the nature of those factors that are capable to induce immune suppression or chronic antigenic stimulation of immune system. Taking into account the full swing of SARS-CoV-2 pandemic and our ignorance of the ability of this virus to induce the sustained stimulation of immune system, we could not exclude the high risk of autoimmune diseases and lymphoid neoplasms in the long-term post-pandemic period. In this context, the role of angiotensin-converting enzyme 2  as well as some recently reported cell receptors for SARS-CoV-2 cell entry should be considered as far as some of them (CD147, CD26) could be tumor-associated antigens.

Immunophenotypic features of leukemic stem cells and bulk of blasts in acute myeloid leukemia.

According to the modern concept, leukemic stem cells (LSC) in acute myeloid leukemia (AML) are distinct from the bulk of leukemic cells in bone marrow and peripheral blood of AML patients. Nevertheless, LSC are responsible for managing all the hierarchy of the bulk of leukemic blast populations. This mini-review provides brief information on the distinctive features of LSC and blast cells in cytologically recognized types of AML. The study of different phenotypes of LSC and blast cells in AML with the aid of up-to-date flow cytometric techniques is important both for the deep insight into the mechanisms of leukemogenesis and development of novel strategies of target therapy. The urgent need for extending the diagnostic panel of monoclonal antibodies used for diagnosing AML is beyond doubt.

Several aspects of descriptive epidemiology of hematological malignancies in adult population of Ukraine, Belarus and Russian Federation after Chornobyl accident.

Chornobyl impact on the health of adult population in Ukraine, Belarus and Russian Federation was a subject of several studies. However, the studies of the effects of Chornobyl on leukemia in adult populations in post-Soviet countries are scarce and the results are contradictory up to present. The results of the epidemiological studies of the oncohematological consequences of Chornobyl accident are briefly reviewed with particular focus on pre-Chornobyl and post-Chornobyl trends in leukemia incidence in Ukraine, Belarus and Russian Federation as well as in small territories of these countries with various levels of radionuclide contamination. This article is a part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

Overview on association of different types of leukemias with radiation exposure.

Exposure to ionizing radiation is associated with increasing risk of various types of hematological malignancies. The results of major studies on association of leukemias and radiation exposure of large populations in Japan and in Ukraine are analyzed. The patterns of different types of leukemia in 295 Chernobyl clean-up workers diagnosed according to the criteria of up-to-date World Health Organization classification within 10-25 years following Chernobyl catastrophe are summarized. In fact, a broad spectrum of radiation-related hematological malignancies has been revealed both in Life Span Study in Japan and in study of Chernobyl clean-up workers in Ukraine. The importance of the precise diagnosis of tumors of hematopoietic and lymphoid tissues according to up-to-date classifications for elucidating the role of radiation as a causative factor of leukemias is emphasized. Such studies are of high importance since according to the recent findings, radiation-associated excess risks of several types of leukemias seem to persist throughout the follow-up period up to 55 years after the radiation exposure.

Leukemic blast cells and controversies in models of hematopoiesis.

Classical and up-to-date models of hematopoietic lineage determination are briefly reviewed with the focus on myeloid-based models challenging the existence of the common progenitor for T cells, B cells and NK cells. The analysis of immunophenotype of leukemic blast cells seems to be a promising approach for interpreting some controversies in the schemes of normal hematopoiesis. The literature data as well as our own findings in the patients with various types of acute leukemias are in favor of the concept postulating that common myeloid-lymphoid progenitors giving rise to T and B cell branches retain the myeloid potential. The similarity of some immunophenotypic features of blast cells in pro-B acute lymphoblastic leukemia and acute monoblastic leukemia is consistent with monocyte origin postulated in the studies of normal hematopoiesis. Study of acute leukemias may be the challenging area of research allowing for new insight into the origin of hematopoietic cell lineages.

[About possible additions to actual scheme of normal blood formation on the basis of study of leukemic blast cells].

The issue of introduction of number of additions into actual scheme of blood formation is discussed. The long standing experience of laboratory diagnostic of oncologic hematological diseases in adults and children and the analysis of published data about normal blood formation are involved into consideration. The existence is surmised of common oligo-linear precursors for B-lymphocytes and monocytes, natural killer cells and monocytes and common cell-precursor of T-lymphocytes and dendrite cells as well. At the same time, the issue concerning the existence of human common cell-precursor of lymphization capable of differentiating into Band T-lymphocytes and natural killer cells is disputable.

Gene expression profiling of B-CLL in Ukrainian patients in post-Chernobyl period.

BACKGROUND: Genetic mechanisms that result in the development and progression of B-cell chronic lymphocytic leukemia (B-CLL) are mainly unknown. We have analyzed gene expression patterns in Ukrainian B-CLL patients with the aim of identifying B-CLL involved / associated genes in order to shed light on the biology of this pathological entity. MATERIAL AND METHODS: The samples of the peripheral blood and bone marrow of 44 Ukrainian B-CLL patients with no characteristics indicative of unfavorable course of the disease such as CD38 were analyzed morphologically and immunocytochemically according to the new WHO classification. Total RNA was isolated, and gene expression levels were determined by microarray method comparing with the sample from 17 healthy donors. RESULTS: We investigated interactions using the Ingenuity Pathway Analysis (IPA) software and found 1191 network eligible up-regulated genes and 3398 Functions/Pathways eligible up-regulated genes, 1225 network eligible down-regulated genes and 2657 Functions/Pathways eligible down-regulated genes. CONCLUSION: In B-CLL patients, gene networks around MYC, HNF1A and HNF4A, YWHAG, NF-κB1 and SP1 are identified as up-regulated; CEBPA, YWHAG, SATB1 and RB1 -- as down-regulated. G protein coupled receptor signaling, arachidonic acid and linoleic acid metabolisms, calcium signaling, metabolism of xenobiotics by cytochrome P450 are found out as significant up-regulated pathways. EIF2 and Cdc42 signaling, regulation of eIF4 and p70S6k signaling, protein ubiquitination pathway and oxidative phosphorylation are the most significant down-regulated pathways obtained in our study. The involvement of NF-κB gene network and upregulated levels of G protein coupled receptor signaling pathway, which has an important role in transcription of NF-κB, are important and need further examination.

Quantitative real time PCR analysis of apoptosis-related gene expression in leukemias in Ukrainian patients.

BACKGROUND: The complete medical consequences of the long-term exposure of population to ionizing radiation in post-Chernobyl period are still a controversial issue. The molecular biological analysis of malignant diseases of hematopoietic and lymphoid tissues in contaminated territories requires the precise diagnosis based on criteria of novel classifications. AIM: To analyze the relative gene expression of six apoptosis-related genes in different types of tumors of hematopoietic and lymphoid tissues in patients living in areas of Ukraine contaminated with radionuclides in post-Chernobyl period. MATERIAL AND METHODS: The samples of the peripheral blood and bone marrow of 189 Ukrainian leukemia patients and 16 patients with reactive lymphocytosis were analyzed morphologically and immunocytochemically for precise delineation of the main forms and cytological variants of hematological malignancies according to new WHO classification. Expression of six apoptosis-related genes was analyzed in the individual samples of 9 different groups of malignant diseases of hematopoietic and lymphoid tissues and one group of patients with reactive lymphocytosis by quantitative RT-PCR. Expression of genes was assessed relative to that in control group of healthy donors. RESULTS: Up-regulation of six analyzed apoptosisrelated genes is observed in all groups of leukemia. In most groups of leukemia being analyzed, BCL-2 up-regulation level is superior to that of BAX. Prominent MYC up-regulation is observed in B-lymphoblastic leukemia/lymphoma, non-Hodgkin's lymphoma, and T-lymphoblastic leukemia/lymphoma groups. In myelodysplastic/myeloproliferative neoplasms, the striking up-regulation of Fas-1 and P38MAPK is evident. Practically all the groups of leukemia are characterized by stable high ratios of P53 up-regulation. CONCLUSION: In Ukrainian patients, up-regulation of six analyzed apoptosis-related genes is observed practically in all types of malignant diseases of hematopoietic and lymphoid tissues under study. Microarray-based analysis of these samples would be of great importance in terms of elucidating genomic interactions in leukemias and their possible association with ionizing radiation.

Study of morphocytochemical and immunophenotypic features of acute leukemia stem cells.

The immunophenotypic profile of hematopoietic stem cells (HSC) and hematopoietic precursor cells as well as leukemic stem cells (LSC) has been extensively studied in several laboratories worldwide. The results of our studies suggest that the standard panel for classification of acute leukemias should be supplemented with several new markers allowing us to identify more precisely the different forms of the leukemias being of the closely related origin, for example AML M6b and AML M7. The common bipotent LSC in AML M7 of low grade and AML M6b may exist analogous to precursor cell common for megakaryocytopoiesis and erythropoiesis. We have also found the similarity between blast cells in pro-B-ALL [t (4;11), 11q23] and AML M5a [t (9;11), 11q23]. Such similarity of immunophenotype and cytogenetic abnormalities in blast cells in pro-B-ALL and AML M5a may be considered as hint explaining the cases of AML M5a as a recurrence of leukemia in children with originally diagnosed pro-B-ALL.

Structure of leukemias and lymphomas in children of Ukraine in post-Chernobyl period.

The structure of hematopoietic malignancies in post-Chernobyl period among pediatric patients in Kyiv city and 24 regions of Ukraine especially those born in 1986 and 1987 and the infants at the age below 1 year is reviewed taking into account the data of the Reference Laboratory obtained in 1993-2004 and based on the modern diagnostic technologies in accordance with FAB, WHO, EGIL, ICD-10 and ICD-O-2 classifications.