Publications by authors named "Andrey B Sudarikov"

8 Publications

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Low V617F Allele Burden in Ph-Negative Chronic Myeloproliferative Neoplasms Is Associated with Additional or Gene Mutations.

Genes (Basel) 2021 Apr 12;12(4). Epub 2021 Apr 12.

National Research Center for Hematology, Novy Zykovski lane 4a, 125167 Moscow, Russia.

(Janus kinase 2) V617F, (Calreticulin) exon 9, and (receptor for thrombopoietin) exon 10 mutations are associated with the vast majority of Ph-negative chronic myeloproliferative neoplasms (MPNs). These mutations affect sequential stages of proliferative signal transduction and therefore, after the emergence of one type of mutation, other types should not have any selective advantages for clonal expansion. However, simultaneous findings of these mutations have been reported by different investigators in up to 10% of MPN cases. Our study includes DNA samples from 1958 patients with clinical evidence of MPN, admitted to the National Research Center for Hematology for genetic analysis between 2016 and 2019. In 315 of 1402 cases (22.6%), mutations were detected. In 23 of these 315 cases (7.3%), the JAK2 V617F mutation was found in addition to the mutation. In 16 from 24 (69.6%) cases, with combined and mutations, V617F allele burden was lower than 1%. A combination of V617F with W515L/K was also observed in 1 out of 1348 cases, only. allele burden in this case was also lower than 1%. Additional mutations may coexist over the low background of JAK2 V617F allele. Therefore, in cases of detecting MPNs with a low allelic load V617F, it may be advisable to search for other molecular markers, primarily mutations in exon 9 of . The load of the combined mutations measured at different time points may indicate that, at least in some cases, these mutations could be represented by different clones of malignant cells.
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http://dx.doi.org/10.3390/genes12040559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069892PMC
April 2021

Inhibitor of BRAF Mutation as a Treatment Option for Hairy Cell Leukemia With Deep Neutropenia and Infectious Complications.

Clin Lymphoma Myeloma Leuk 2021 Mar 3. Epub 2021 Mar 3.

National Research Center for Hematology, Moscow, Russia.

Standard therapy in hairy cell leukemia (HCL) is often impossible at the time of deep neutropenia/agranulocytosis with or without infectious complications; it is thus a complex therapeutic problem. Vemurafenib has been used to treat resistant HCL since 2012. Because vemurafenib does not have a myelotoxic effect, we thought that it could be used to treat HCL associated with deep neutropenia/agranulocytosis with or without the development of infectious complications as a preliminary stage before treatment with cladribine. We conducted a retrospective analysis of treatment with vemurafenib followed by a standard course of cladribine provided to 22 patients with deep neutropenia/agranulocytosis with or without infectious complications at diagnosis. Vemurafenib was provided to 22 patients with HCL. The response to therapy was evaluated by complete blood cell count (absolute neutrophil count [ANC], hemoglobin concentration, platelet count, absence of hairy cells), spleen size (assessed by ultrasound), and reduce infectious complications. After that, a standard course of cladribine was provided. Among the 22 patients, the male/female sex ratio was 2:1, and median (range) age was 52 (24-78) years. There were 7 patients with severe infectious manifestations admitted to the intensive care unit, including 1 patient during extracorporeal membrane oxygenation. The median (range) ANC at diagnosis was 0.3 (0.04-0.7) × 10/L. Vemurafenib was provided at a dosage of 240 mg 1 or 2 times a day. In 20 patients, vemurafenib was provided for 3 months or more. In 1 case, the effect was not obtained during 1 month of treatment, and the patient died from severe infectious complications during prolonged agranulocytosis. In 21 patients treated with vemurafenib, an increase of ANC was observed and the infectious complications resolved, thus allowing the application of cladribine therapy. After a standard course (0.1 mg/kg per day for 7 days) of cladribine chemotherapy, 18 patients (90%) experienced complete clinical remission and 2 patients (10%) experienced partial remission with residual splenomegaly. In 1 patient, vemurafenib therapy was still ongoing 2 months after initiating therapy. In cases of proven BRAF mutation, vemurafenib can be successfully used as an effective preliminary therapy in patients with deep neutropenia/agranulocytosis with or without infectious complications before standard therapy with purine analogs.
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http://dx.doi.org/10.1016/j.clml.2021.02.005DOI Listing
March 2021

Simultaneous Presentation of Leukemic Non-Nodal Mantle Cell Lymphoma and Gamma-Delta T-Large Granular Lymphocytic Leukemia in a Patient with Rheumatoid Arthritis.

Cancer Manag Res 2020 30;12:9449-9457. Epub 2020 Sep 30.

Laboratory of Molecular Hematology, National Research Center for Hematology, Moscow, Russia.

The peculiar features of T-cell large granular lymphocytic leukemia (T-LGLL) are its association with autoimmune disorders (particularly with rheumatoid arthritis (RA)) and a broad spectrum of B-cell lymphoproliferative disorders. However, association of T-LGLL with mantle cell lymphoma (MCL) is extremely rare. Here, we describe a case of an 80-year-old man admitted with suspected Felty's syndrome. The blood count showed white blood cells at 2.2×10/L, with 3% neutrophils, 88% lymphocytes, and at 0.66×10/L LGLs. The spleen had been removed 43 months prior to the admission due to suspected B-cell splenic lymphoma. Re-examination of the spleen revealed cyclin D1+ and SOX11- lymphocytes in the inner part of the unexpanded mantle zones of the white pulp follicles, thus displaying a so-called in situ histologic pattern of MCL, and in small clusters in the red pulp. The splenic cords were moderately expanded by lymphocytes expressing CD3, TIA1, and granzyme B but not CD4 and CD8. Monoclonal rearrangements of the gene and the genes, polyclonal rearrangements of the gene, mutation of the   gene (c.1940A>T; p.N647I), and t(11;14)(q13;q32) translocation were identified in the spleen sample. Flow cytometry of bone marrow revealed a population of TCR γδ+, CD3+, CD4-, CD5-, CD7+, CD8-, CD16-, CD56-, and CD57- lymphocytes. Fragment analysis demonstrated identical gene clonal rearrangement patterns in the spleen and bone marrow samples. In this study, we describe the first case of simultaneous presentation of γδ T-LGLL and leukemic non-nodal MCL (L-NN-MCL) in a patient with RA and present morphological findings of L-NN-MCL in the spleen.
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http://dx.doi.org/10.2147/CMAR.S261910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533220PMC
September 2020

High Incidence of Clonal CD8+ T-cell Proliferation in Non-malignant Conditions May Reduce the Significance of T-cell Clonality Assay for Differential Diagnosis in Oncohematology.

Clin Lymphoma Myeloma Leuk 2020 04 8;20(4):203-208. Epub 2020 Jan 8.

National Research Center for Hematology, Moscow, Russia.

Polymerase chain reaction (PCR) analysis of rearranged T-cell receptor (TCR) genes is a valuable diagnostic tool for differential diagnosis of T-cell large granular lymphocytic (T-LGL) leukemia and reactive lymphocytosis. Age-related narrowing of T-cells repertoire and expansion of immune or autoimmune clones may lead to false-positive results. The objective of this study was to evaluate the specificity and positive predictive value of PCR-based clonality assessment for a differential diagnostics of T-LGL leukemia. Rearrangements of TCRG and TCRB genes using the BIOMED-2 protocol were assessed in healthy individuals including the elderly (n = 62) and patients with rheumatic diseases (n = 14), transitory reactive CD8+ lymphocytosis (n = 17), and T-LGL leukemia (n = 42). Monoclonal TCRG/TCRB rearrangements in blood were identified in 11.3%/4.8% (7/3 of 62) of healthy individuals; 21.4%/14.3% (3/2 of 14) of patients with rheumatic diseases, and 17.6%/11.8% (3/2 of 17) of patients with reactive lymphocytosis. Immunomagnetic selection of lymphocytes in healthy individuals (31 of 33) revealed that clonal T-cells belong to CD8+ and CD57+ population. No clonal Vβ-Jβ TCRB rearrangements were found in the control group, only Dβ-Jβ TCRB and TCRG. Given the high detectability (96.7%) of Vβ-Jβ TCRB monoclonal rearrangements in patients with αβ-T-LGL leukemia, this marker had the greatest specificity and positive predictive value (100%; 99.2%). The presence of clonal CD8+CD57+ cells in blood is common for healthy individuals and patients with reactive conditions and may not associate with any malignancy. Different specificity of TCRG/ Dβ-Jβ TRB/ Vβ-Jβ TCRB PCR reactions should be taken into account for T-cell clonality data interpretation.
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http://dx.doi.org/10.1016/j.clml.2019.12.021DOI Listing
April 2020

Composite Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma and Epstein-Barr virus-negative diffuse large B-cell lymphoma in the parotid salivary gland of a patient with Sjögren's syndrome and rheumatoid arthritis: a case report.

J Med Case Rep 2020 Jan 17;14(1):12. Epub 2020 Jan 17.

Department of Nuclear Diagnostics, A.N. Bakulev National Medical Research Center of Cardiovascular Surgery, Roublyevskoe Shosse 135, Moscow, 121552, Russia.

Background: Epstein-Barr virus is associated with many human hematopoietic neoplasms; however, Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma is extremely rare. In routine clinical practice, detection of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in a tissue sample presumes a clonal relation between these neoplasms and that diffuse large B-cell lymphoma developed by transformation of the mucosa-associated lymphoid tissue lymphoma. However, evidence to support this presumption is sparse and controversial. Assessment of the clonal relationship of the lymphoid components of a composite lymphoma is important for understanding its pathogenesis and correct diagnosis.

Case Presentation: We present an unusual case of composite lymphoma (Epstein-Barr virus-positive mucosa-associated lymphoid tissue lymphoma/Epstein-Barr virus-negative diffuse large B-cell lymphoma) in the parotid salivary gland of a 62-year-old Caucasian woman with Sjögren's syndrome and rheumatoid arthritis. Simultaneous occurrence of mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma in the parotid salivary gland led us to initially assume a clonal relationship between diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma. Epstein-Barr virus was detected by in situ hybridization and polymerase chain reaction in the mucosa-associated lymphoid tissue lymphoma, but not in diffuse large B-cell lymphoma, suggesting that these lymphomas were not clonally related. Fragment analysis of frame region 3 polymerase chain reaction products from microdissected mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma components revealed different clonal pattern rearrangements of the immunoglobulin heavy chain gene.

Conclusions: Our patient's case highlights the importance of assessing the clonal relationships of the lymphoid components of a composite lymphoma and Epstein-Barr virus screening in mucosa-associated lymphoid tissue lymphoma in patients with autoimmune disease.
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http://dx.doi.org/10.1186/s13256-019-2331-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966905PMC
January 2020

A simple and efficient method for DNA extraction from skin and paraffin-embedded tissues applicable to T-cell clonality assays.

Exp Dermatol 2012 Jan 13;21(1):57-60. Epub 2011 Oct 13.

Department of Molecular Hematology, National Hematology Research Center, Moscow, Russia.

PCR-based clonality assay of rearranged T-cell receptor genes gamma and beta (TCRG and TCRB) in a number of cases could be essential to discriminate between cutaneous T-cell lymphomas and reactive lymphoproliferative lesions in the skin. However, extraction of good-quality DNA from skin specimens (especially formalin-fixed paraffin-embedded) remains a challenge. Common procedures, being labour-intensive and time-consuming and requiring toxic solvents such as phenol and chloroform, still may end up with DNA sample of insufficient quality. We herewith present a simple and efficient method for DNA isolation based on ammonia extraction of tissue, followed by neutralization and simultaneous salting out of proteins with acetic acid. We have analysed 30 samples - 24 fresh (16 skin, two spleen and six lymph node) and six paraffin-embedded. Standard procedure (proteinase K digestion, followed by phenol/chloroform extraction) has been carried out simultaneously. We observed good PCR signal for TCRG rearrangements in 30 samples processed with the new protocol and only in 20 extracted with proteinase K/phenol/chloroform. For TCRB, the success rate was 29 of 30 with the new protocol, compared to 11 of 30 with conventional protocol. The proposed method of DNA extraction should improve the value of T-cell clonality assay, because insufficient DNA quality and quantity may bias analysis towards monoclonality and therefore cause false-positive results.
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http://dx.doi.org/10.1111/j.1600-0625.2011.01375.xDOI Listing
January 2012

Polymorphisms in xenobiotic-metabolizing genes and the risk of chronic lymphocytic leukemia and non-Hodgkin's lymphoma in adult Russian patients.

Am J Hematol 2008 Apr;83(4):279-87

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

Polymorphisms in genes coding xenobiotic-metabolizing enzymes are considered as risk factors modifying susceptibility to cancer. We developed a biochip for the analysis of 18 mutations in 10 genes of metabolizing system: CYP1A1, CYP2D6, GSTT1, GSTM1, MTHFR, MTRR, NQO1, CYP2C9, CYP2C19, and NAT2. Using allele-specific hybridization on the biochip 76 T-cell non-Hodgkin's lymphoma (NHL) patients, 83 B-cell chronic lymphocytic leukemia (B-CLL) patients, and 177 healthy donors were tested. Polymorphic CYP1A1 alleles were more frequent in B-CLL patients relative to normal controls, for example, a combination of polymorphic variants 4887C > A, 4889A > G, and 6235T > C (OR = 1.76, 95% CI = 1.0-3.1). The GSTM1 null genotype was more frequent in NHL patients relative to controls (OR = 1.82, 95% CI = 1.1-3.1). The combination of unfavorable polymorphic CYP1A1 variants and GSTM1 null genotype was found more frequently in B-CLL patients relative to controls (OR = 2.52, 95% CI = 1.3-4.9). In addition, male B-CLL patients demonstrated a significantly increased occurrence of heterozygous and homozygous allele *2 of CYP2C9 gene (OR = 2.38, 95% CI = 1.1-5.2) as well as a combination of alleles *2 and *3 of the gene (OR = 2.09, 95% CI = 1.1-3.9). Thus, our findings show the association between polymorphic alleles of CYP1A1, GSTM1, and CYP2C9 genes and the risk to develop NHL or B-CLL. The developed biochip can be considered as a convenient analytical tool for research studies and predictive analysis in oncohematology.
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http://dx.doi.org/10.1002/ajh.21113DOI Listing
April 2008

Analysis of T-cell receptor-gamma gene rearrangements using oligonucleotide microchip: a novel approach for the determination of T-cell clonality.

J Mol Diagn 2007 Apr;9(2):249-57

Department of Biological Microchips, Engelhardt Institute of Molecular Biology, Moscow, Russia.

T-cell clonality estimation is important for the differential diagnosis between malignant and nonmalignant T-cell proliferation. Routinely used methods include polymerase chain reaction (PCR) analysis of T-cell receptor-gamma (TCR-gamma) gene rearrangements followed by Genescan analysis, polyacrylamide gel electrophoresis, or heteroduplex analysis to visualize amplification products. Here, we present a new method for the analysis after PCR of TCR-gamma rearrangements using hybridization on oligonucleotide microchip. A microchip was designed to contain specific probes for all functional variable (V) and joining (J) gene segments involved in rearrangements of the TCR-gamma locus. Fluorescently labeled fragments of rearranged gamma-chain from patients and donors were obtained in a multiplex nested PCR and hybridized with a microchip. The results were detected using a portable microchip analyzer. Samples from 49 patients with T-cell lymphomas or leukemias and 47 donors were analyzed for T-cell clonality by microchip and single-strand conformation polymorphism analysis, which served as a standard reference method. Comparison of two techniques showed full concordance of the results. The microchip-based approach also allowed the identification of V and J gene segments involved in the particular TCR-gamma rearrangement. The sensitivity of the method is sufficient to determine 10% of clonal cells in the sample.
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http://dx.doi.org/10.2353/jmoldx.2007.060087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1867449PMC
April 2007