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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 August 2023) | Viewed by 28231

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Dr. Andrey Sudarikov

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National Medical Research Center for Hematology, Novy Zykovski Lane, 4a, 125167 Moscow, Russia
Interests: prognostic factors in leukemia and lymphoma; methods of molecular diagnostics in blood diseases; molecular monitoring of therapy efficacy (including transplantation)

Special Issue Information

Dear Colleagues,

The study of the genetic basis of blood disorders has been at the forefront of medical genetics since the work of Alexander Maksimov in 1909, who postulated the clonal nature of hematopoiesis. The hematopoietic system is a unique object for the study of both germinal factors leading to various hereditary diseases and somatic mutations associated with malignancies. Advances in genetics and molecular biology in recent years have made it possible to significantly clarify understanding of the pathogenesis of hematological diseases. In connection with the development of targeted therapy approaches, the study of the molecular basis of blood diseases and the search for and characterization of appropriate genetic targets for therapeutic intervention are becoming increasingly important.

We encourage the submission of original manuscripts containing new, unpublished data relating to a wide range of genetic studies in hematology. Manuscripts on molecular genetic studies of hereditary blood diseases, neoplasia of lymphoid and myeloid tissue, genetic factors associated with the prognosis of disease or the effectiveness of therapy, etc., are invited. The intended publication formats to be considered include original articles, short communications, and literature reviews.

Dr. Andrey Sudarikov
Guest Editor

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Keywords

hereditary blood disorders
leukemia
lymphoma
myeloproliferative neoplasms
somatic mutations in clonal hematopoiesis
molecular targets for therapy

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Published Papers (10 papers)

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Research

11 pages, 2055 KiB

Open AccessArticle

Occurrence of L1M Elements in Chromosomal Rearrangements Associated to Chronic Myeloid Leukemia (CML): Insights from Patient-Specific Breakpoints Characterization

by Alberto L’Abbate, Vittoria Moretti, Ester Pungolino, Giovanni Micheloni, Roberto Valli, Annalisa Frattini, Matteo Barcella, Francesco Acquati, Rolland A Reinbold, Lucy Costantino, Fulvio Ferrara, Alessandra Trojani, Mario Ventura, Giovanni Porta and Roberto Cairoli

Genes 2023, 14(7), 1351; https://doi.org/10.3390/genes14071351 - 27 Jun 2023

Cited by 1 | Viewed by 1962

Abstract

Chronic myeloid leukemia (CML) is a rare myeloproliferative disorder caused by the reciprocal translocation t(9;22)(q34;q11) in hematopoietic stem cells (HSCs). This chromosomal translocation results in the formation of an extra-short chromosome 22, called a Philadelphia chromosome (Ph), containing the BCR-ABL1 fusion gene responsible for the expression of a constitutively active tyrosine kinase that causes uncontrolled growth and replication of leukemic cells. Mechanisms behind the formation of this chromosomal rearrangement are not well known, even if, as observed in tumors, repetitive DNA may be involved as core elements in chromosomal rearrangements. We have participated in the explorative investigations of the PhilosoPhi34 study to evaluate residual Ph+ cells in patients with negative FISH analysis on CD34+/lin- cells with gDNA qPCR. Using targeted next-generation deep sequencing strategies, we analyzed the genomic region around the t(9;22) translocations of 82 CML patients and one CML cell line and assessed the relevance of interspersed repeat elements at breakpoints (BP). We found a statistically higher presence of LINE elements, in particular belonging to the subfamily L1M, in BP cluster regions of both chromosome 22 and 9 compared to the whole human genome. These data suggest that L1M elements could be potential drivers of t(9;22) translocation leading to the generation of the BCR-ABL1 chimeric gene and the expression of the active BCR-ABL1-controlled tyrosine kinase chimeric protein responsible for CML. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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12 pages, 737 KiB

Open AccessArticle

Transcription of WNT Genes in Hematopoietic Niche’s Mesenchymal Stem Cells in Multiple Myeloma Patients with Different Responses to Treatment

by Natella I. Enukashvily, Liubov. A. Belik, Natalia Yu. Semenova, Ivan I. Kostroma, Ekaterina V. Motyko, Sergey V. Gritsaev, Stanislav S. Bessmeltsev, Sergey V. Sidorkevich and Irina S. Martynkevich

Genes 2023, 14(5), 1097; https://doi.org/10.3390/genes14051097 - 17 May 2023

Viewed by 1758

Abstract

Mesenchymal stromal cells (MSCs) are involved in bone tissue remodeling due to their ability to differentiate into osteoblasts and to influence osteoclasts’ activity. Multiple myeloma (MM) is associated with bone resorption. During disease progression, MSCs acquire a tumor-associated phenotype, losing their osteogenic potential. The process is associated with impaired osteoblasts/osteoclasts balance. The WNT signaling pathway plays a major role in maintaining the balance. In MM, it functions in an aberrant way. It is not known yet whether the WNT pathway is restored in patients’ bone narrow after treatment. The aim of the study was to compare the level of WNT family gene transcription in the bone marrow MSCs of healthy donors and MM patients before and after therapy. The study included healthy donors (n = 3), primary patients (n = 3) and patients with different response status to therapy (bortezomib-containing induction regimens) (n = 12). The transcription of the WNT and CTNNB1 (encoding β-catenin) genes was accessed using qPCR. The mRNA quantity of ten WNT genes, as well as CTNNB1 mRNA encoding β-catenin, a key mediator in canonical signaling, was evaluated. The observed differences between the groups of patients indicated that aberrant functioning of the WNT pathway was retained after treatment. The differences that we detected for WNT2B, WNT9B and CTNNB1 suggested their possible application as prognostic molecular markers. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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14 pages, 2634 KiB

Open AccessArticle

Molecular Heterogeneity of Pediatric AML with Atypical Promyelocytes Accumulation in Children—A Single Center Experience

by Aleksandra Borkovskaia, Sofia Bogacheva, Tatiana Konyukhova, Elina Dadakhanova, Marina Gaskova, Olga Soldatkina, Maria Dubrovina, Alexander Popov, Ekaterina Mikhailova, Evgenia Inushkina, Marat Kazanov, Evgeniy Matveev, Galina Novichkova, Michael Maschan, Alexey Maschan, Yulia Olshanskaya and Elena Zerkalenkova

Genes 2023, 14(3), 675; https://doi.org/10.3390/genes14030675 - 8 Mar 2023

Cited by 1 | Viewed by 2432

Abstract

Acute promyelocytic leukemia (APL) pathogenesis is based on RARA gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL. However, in some cases acute myeloid leukemia (AML) demonstrates APL-like morphological features such as atypical promyelocytes accumulation. This type of AML is characterized by the involvement of other RAR family members or completely different genes. In the present study, we used conventional karyotyping, FISH and high-throughput sequencing in a group of 271 de novo AML with atypical promyelocytes accumulation. Of those, 255 cases were shown to carry a typical chromosomal translocation t(15;17)(q24;q21) with PML::RARA chimeric gene formation (94.1%). Other RARA-positive cases exhibited cryptic PML::RARA fusion without t(15;17)(q24;q21) (1.8%, n = 5) and variant t(5;17)(q35;q21) translocation with NPM1::RARA chimeric gene formation (1.5%, n = 4). However, 7 RARA-negative AMLs with atypical promyelocytes accumulation were also discovered. These cases exhibited TBL1XR1::RARB and KMT2A::SEPT6 fusions as well as mutations, e.g., NPM1 insertion and non-recurrent chromosomal aberrations. Our findings demonstrate the genetic diversity of AML with APL-like morphological features, which is of high importance for successful therapy implementation. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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10 pages, 253 KiB

Open AccessArticle

Role of Genetic Thrombophilia Markers in Thrombosis Events in Elderly Patients with COVID-19

by Irina Fevraleva, Daria Mamchich, Dmitriy Vinogradov, Yulia Chabaeva, Sergey Kulikov, Tatiana Makarik, Vahe Margaryan, Georgiy Manasyan, Veronika Novikova, Svetlana Rachina, Georgiy Melkonyan and Karine Lytkina

Genes 2023, 14(3), 644; https://doi.org/10.3390/genes14030644 - 4 Mar 2023

Cited by 2 | Viewed by 2195

Abstract

Thrombosis is an extremely dangerous complication in elderly patients with COVID-19. Since the first months of the pandemic, anticoagulants have been mandatory in treatment protocols for patients with COVID-19, unless there are serious contraindications. We set out to discover if genetic thrombophilia factors continue to play a triggering role in the occurrence of thrombosis in patients with COVID-19 with prophylactic or therapeutic anticoagulants. We considered the following genetic markers as risk factors for thrombophilia: G1691A in the FV gene, C677T and A1298C in the MTHFR gene, G20210A and C494T in the FII gene, and (−675) 4G/5G in the PAI-I gene. In a cohort of 176 patients, we did not obtain a reliable result indicating a higher risk of thrombotic complications when taking therapeutic doses of anticoagulants in carriers of genetic markers for thrombophilia except the C494T mutation in the FII gene. However, there was still a pronounced tendency to a higher incidence of thrombosis in patients with markers of hereditary thrombophilia, such as FV G1691A and FII G20210A mutations. The presence of the C494T (Thr165Met) allele in the FII gene in this group of patients showed a statistically significant effect of the mutation on the risk of thrombotic complications despite anticoagulant therapy. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

13 pages, 297 KiB

Open AccessArticle

“What We Know and What We Do Not Know about Evolutionary Genetic Adaptation to High Altitude Hypoxia in Andean Aymaras”

by Ricardo Amaru, Jihyun Song, N. Scott Reading, Victor R. Gordeuk and Josef T. Prchal

Genes 2023, 14(3), 640; https://doi.org/10.3390/genes14030640 - 3 Mar 2023

Cited by 3 | Viewed by 2576

Abstract

Three well-studied populations living at high altitudes are Tibetans, Andeans (Aymaras and Quechuas), and Ethiopians. Unlike Tibetans and Ethiopians who have similar hemoglobin (Hb) levels as individuals living at sea level, Aymara Hb levels increase when living at higher altitudes. Our previous whole genome study of Aymara people revealed several selected genes that are involved in cardiovascular functions, but their relationship with Hb levels was not elucidated. Here, we studied the frequencies of known evolutionary-selected variants in Tibetan and Aymara populations and their correlation with high Hb levels in Aymara. We genotyped 177 Aymaras at three different altitudes: 400 m (Santa Cruz), 4000 m (La Paz), and 5000 m (Chorolque), and correlated the results with the elevation of residence. Some of the Tibetan-selected variants also exist in Aymaras, but at a lower prevalence. Two of 10 Tibetan selected variants of EPAS1 were found (rs13005507 and rs142764723) and these variants did not correlate with Hb levels. Allele frequencies of 5 Aymara selected SNPs (heterozygous and homozygous) at 4000 m (rs11578671_BRINP3, rs34913965_NOS2, rs12448902_SH2B1, rs10744822_TBX5, and rs487105_PYGM) were higher compared to Europeans. The allelic frequencies of rs11578671_BRINP3, rs34913965_NOS2, and rs10744822_SH2B1 were significantly higher for Aymaras living at 5000 m than those at 400 m elevation. Variant rs11578671, close to the BRINP3 coding region, correlated with Hb levels in females. Variant rs34913965 (NOS2) correlated with leukocyte counts. Variants rs12448902 (SH2B1) and rs34913965 (NOS2) associated with higher platelet levels. The correlation of these SNPs with blood cell counts demonstrates that the selected genetic variants in Aymara influence hematopoiesis and cardiovascular effects. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

12 pages, 2919 KiB

Open AccessArticle

Accumulation of STR-Loci Aberrations in Subclones of Jurkat Cell Line as a Model of Tumor Clonal Evolution

by Natalya Risinskaya, Olga Glinshchikova, Tatiana Makarik, Yana Kozhevnikova, Julia Chabaeva and Sergey Kulikov

Genes 2023, 14(3), 571; https://doi.org/10.3390/genes14030571 - 24 Feb 2023

Cited by 1 | Viewed by 2027

Abstract

Many genetic markers are known to distinguish tumor cells from normal. Genetic lesions found at disease onset often belong to a predominant tumor clone, and further observation makes it possible to assess the fate of this clone during therapy. However, minor clones escape monitoring and become unidentified, leading to relapses. Here we report the results of in vitro study of clonal evolution in cultured tumor cell line (Jurkat) compared to the cell line of non-tumor origin (WIL2-S). Cell lines were cultured and cloned by limiting dilutions. Subclones were tested by short tandem repeats (STR) profiling. Spontaneous STR aberrations in cells of non-tumor origin occur in less than 1 of 100 cultured cells. While in the cells of tumor origin, new aberrations appear in 1 or even more of 3 cultured cells. At the same time, a significant relationship was found between the accumulation of aberrations in the pool of subclones and the rate of cell growth. One can speculate that this approach could be applied for the analysis of primary patient tumor cell culture to obtain information concerning the evolutionary potential of the tumor cells that may be useful for the selection of a therapy approach. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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11 pages, 545 KiB

Open AccessArticle

Genetic Lesions in Russian CLL Patients with the Most Common Stereotyped Antigen Receptors

by Bella V. Biderman, Ekaterina B. Likold, Nataliya A. Severina, Tatiana N. Obukhova and Andrey B. Sudarikov

Genes 2023, 14(2), 532; https://doi.org/10.3390/genes14020532 - 20 Feb 2023

Cited by 1 | Viewed by 1721

Abstract

Chronic lymphocytic leukemia (CLL) is one of the most common B-cell malignancies in Western countries. IGHV mutational status is the most important prognostic factor for this disease. CLL is characterized by an extreme narrowing of the IGHV genes repertoire and the existence of subgroups of quasi-identical stereotyped antigenic receptors (SAR). Some of these subgroups have already been identified as independent prognostic factors for CLL. Here, we report the frequencies of TP53, NOTCH1, and SF3B1 gene mutations and chromosomal aberrations assessed by NGS and FISH in 152 CLL patients with the most common SAR in Russia. We noted these lesions to be much more common in patients with certain SAR than average in CLL. The profile of these aberrations differs between the subgroups of SAR, despite the similarity of their structure. For most of these subgroups mutations prevailed in a single gene, except for CLL#5 with all three genes affected by mutations. It should be noted that our data concerning the mutation frequency in some SAR groups differ from that obtained previously, which could be due to the population differences between patient cohorts. The research in this area should be important for better understanding the pathogenesis of CLL and therapy optimization. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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13 pages, 1460 KiB

Open AccessArticle

Loss of Heterozygosity in the Circulating Tumor DNA and CD138+ Bone Marrow Cells in Multiple Myeloma

by Maiia Soloveva, Maksim Solovev, Elena Nikulina, Natalya Risinskaya, Bella Biderman, Igor Yakutik, Tatiana Obukhova and Larisa Mendeleeva

Genes 2023, 14(2), 351; https://doi.org/10.3390/genes14020351 - 29 Jan 2023

Cited by 2 | Viewed by 2134

Abstract

Multiple myeloma (MM) is characterized by heterogeneity of tumor cells. The study of tumor cells from blood, bone marrow, plasmacytoma, etc., allows us to identify similarities and differences in tumor lesions of various anatomical localizations. The aim of this study was to compare the loss of heterozygosity (LOH) by tumor cells by assessing STR profiles of different MM lesions. We examined paired samples of plasma circulating tumor DNA (ctDNA) and CD138+ bone marrow cells in MM patients. For patients with plasmacytomas (66% of 38 patients included), the STR profile of plasmacytomas was also studied when biopsy samples were available. Diverse patterns of LOH were found in lesions of different localization for most patients. LOH in plasma ctDNA, bone marrow, and plasmacytoma samples was found for 55%, 71%, and 100% of patients, respectively. One could expect a greater variety of STR profiles in aberrant loci for patients with plasmacytomas. This hypothesis was not confirmed—no difference in the frequency of LOH in MM patients with or without plasmacytomas was found. This indicates the genetic diversity of tumor clones in MM, regardless of the presence of extramedullar lesions. Therefore, we conclude that risk stratification based on molecular tests performed solely on bone marrow samples may not be sufficient for all MM patients, including those without plasmacytomas. Due to genetic heterogeneity of MM tumor cells from various lesions, the high diagnostic value of liquid biopsy approaches becomes obvious. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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16 pages, 1574 KiB

Open AccessArticle

Spectrum of Causative Mutations in Patients with Hemophilia A in Russia

by Olesya Pshenichnikova, Valentina Salomashkina, Julia Poznyakova, Daria Selivanova, Daria Chernetskaya, Elena Yakovleva, Oksana Dimitrieva, Elena Likhacheva, Farida Perina, Nadezhda Zozulya and Vadim Surin

Genes 2023, 14(2), 260; https://doi.org/10.3390/genes14020260 - 19 Jan 2023

Viewed by 3384

Abstract

Hemophilia A (HA) is one of the most widespread, X-linked, inherited bleeding disorders, which results from defects in the F8 gene. Nowadays, more than 3500 different pathogenic variants leading to HA have been described. Mutation analysis in HA is essential for accurate genetic counseling of patients and their relatives. We analyzed patients from 273 unrelated families with different forms of HA. The analysis consisted of testing for intron inversion (inv22 and inv1), and then sequencing all functionally important F8 gene fragments. We identified 101 different pathogenic variants in 267 patients, among which 35 variants had never been previously reported in international databases. We found inv22 in 136 cases and inv1 in 12 patients. Large deletions (1–8 exons) were found in 5 patients, and we identified a large insertion in 1 patient. The remaining 113 patients carried point variants involving either single nucleotide or several consecutive nucleotides. We report herein the largest genetic analysis of HA patients issued in Russia. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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31 pages, 3445 KiB

Open AccessArticle

Predicting Genetic Disorder and Types of Disorder Using Chain Classifier Approach

by Ali Raza, Furqan Rustam, Hafeez Ur Rehman Siddiqui, Isabel de la Torre Diez, Begoña Garcia-Zapirain, Ernesto Lee and Imran Ashraf

Genes 2023, 14(1), 71; https://doi.org/10.3390/genes14010071 - 26 Dec 2022

Cited by 15 | Viewed by 6270

Abstract

Genetic disorders are the result of mutation in the deoxyribonucleic acid (DNA) sequence which can be developed or inherited from parents. Such mutations may lead to fatal diseases such as Alzheimer’s, cancer, Hemochromatosis, etc. Recently, the use of artificial intelligence-based methods has shown superb success in the prediction and prognosis of different diseases. The potential of such methods can be utilized to predict genetic disorders at an early stage using the genome data for timely treatment. This study focuses on the multi-label multi-class problem and makes two major contributions to genetic disorder prediction. A novel feature engineering approach is proposed where the class probabilities from an extra tree (ET) and random forest (RF) are joined to make a feature set for model training. Secondly, the study utilizes the classifier chain approach where multiple classifiers are joined in a chain and the predictions from all the preceding classifiers are used by the conceding classifiers to make the final prediction. Because of the multi-label multi-class data, macro accuracy, Hamming loss, and α-evaluation score are used to evaluate the performance. Results suggest that extreme gradient boosting (XGB) produces the best scores with a 92% α-evaluation score and a 84% macro accuracy score. The performance of XGB is much better than state-of-the-art approaches, in terms of both performance and computational complexity. Full article

(This article belongs to the Special Issue Genetics of Blood Disorders)

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