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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 16572

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Special Issue Editor

Prof. Dr. Mookon Song

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Guest Editor

Department of Hematology, Hanyang University Hanmaeum Changwon Hospital, 04763 Changwon, Republic of Korea
Interests: diffuse large B-cell lymphoma; B-cell lymphoma; leukemia; non-Hodgkin lymphoma; plasmacytoma

Special Issue Information

Dear Colleagues,

In recent years, Hematologic malignancies such as myelodysplastic syndromes (MDS), acute myeloid or lymphoid leukemia (AML, ALL), or myeloproliferative neoplasms (MPN) has not only become a pure research issue in Hematology, but a real basis for innovative and “patient-oriented” treatments. Allogeneic hematopoietic cell transplantation, targeted therapy, and/or new immunotherapies have been used in high-risk patients. To improve current therapies and develop new strategies, a more detailed analysis of the interaction of hematological malignancies with cellular and extracellular components is required. Therefore, this Research Topic aims to highlight the recent advances, to cover the progress of basic and preclinical research, to address the relevant and novel therapeutic strategies as well as to identify and discuss the pitfalls and limiting factors. Given the number of recent experimental studies in this space, we aim to provide comprehensive reviews on the cellular/molecular biology of lymphoma and myeloma as well including original articles which will provide a basis for refining and further developing our understanding of the biology of cell myeloma/leukemia with attendant prognostic and therapeutic implications.

Prof. Dr. Mookon Song
Guest Editor

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Published Papers (5 papers)

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Research

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13 pages, 1719 KiB

Open AccessArticle

Molecular Characterisation of Epstein–Barr Virus in Classical Hodgkin Lymphoma

by Valerija Begić, Petra Korać, Slavko Gašparov, Marija Rozman, Petra Simicic and Snjezana Zidovec-Lepej

Int. J. Mol. Sci. 2022, 23(24), 15635; https://doi.org/10.3390/ijms232415635 - 9 Dec 2022

Cited by 5 | Viewed by 2069

Abstract

Hodgkin lymphomas (HLs) are a heterogeneous group of lymphoid neoplasia associated with Epstein–Barr virus (EBV) infection. EBV, considered to be an important etiological co-factor in approximately 1% of human malignancies, can be classified into two genotypes based on EBNA-2, EBNA-3A and EBNA-3C sequences, and into genetic variants based on the sequence variation of the gene coding for the LMP1 protein. Here, we present the results on the distribution of EBV genotypes 1 and 2 as well as LMP1 gene variants in 50 patients with EBV-positive classical HL selected from a cohort of 289 histologically verified cases collected over a 9-year period in a tertiary clinical center in the Southeast of Europe. The population-based sequencing of the EBNA-3C gene showed the exclusive presence of EBV genotype 1 in all cHL samples. The analysis of EBV LMP1 variant distribution showed a predominance of the wild-type strain B95-8 and the Mediterranean subtype with 30 bp deletion. These findings could contribute to the understanding of EBV immunobiology in cHL as well as to the development of a prophylactic and therapeutic vaccine. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lymphomas and Leukemia)

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12 pages, 795 KiB

Open AccessCommunication

Genomic Landscape of Mixed-Phenotype Acute Leukemia

by Marah Hennawi, Nagehan Pakasticali, Hammad Tashkandi and Mohammad Hussaini

Int. J. Mol. Sci. 2022, 23(19), 11259; https://doi.org/10.3390/ijms231911259 - 24 Sep 2022

Cited by 5 | Viewed by 3657

Abstract

Mixed-phenotype leukemia (MPAL) is a type of acute leukemia in which the blast population shows mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. MPALs are rare and carry a poor prognosis, thus, often pose both a diagnostic and therapeutic challenge. Conventionally, the diagnosis of MPAL requires either a single blast population with a lineage-defining phenotypic expression of multiple lineages (myeloid, B-cell and/or T-cell) (biphenotypic) or two distinct blast populations that each independently satisfy criteria for designation as AML, B-ALL, and/or T-ALL (bilineage). Given the rarity of MPAL, minimal studies have been performed to describe the genomic landscape of these neoplasms. IRB approval was obtained. Central MCC database was searched for any patient with a diagnosis of acute undifferentiated leukemia (AUL), acute leukemia of ambiguous lineage (ALAL), and MPAL. All patient diagnoses were manually reviewed by a hematopathologist to confirm the diagnosis of MPAL. Genomic and molecular data were collated from the EMR and bioinformatically from MCC genomics repositories. Twenty-eight patients with MPAL were identified. Thirteen were female and 15 were male. Average age was 56 years old (range = 28–81). Ten cases were biclonal and 18 were biphenotypic. Diagnoses were as follows: B/myeloid (n = 18), T/myeloid (n = 9), and T/B (n = 1). Cytogenetic analysis (Karyotype +/− FISH) was available for 27 patients. The most frequent recurrent abnormalities were complex karyotype (n = 8), BCR/ABL1 translocation (n = 6), Del 5q/−5 (n = 4), Polysomy 21 (n = 4). Mutational analysis was available for 18 patients wherein mutations were detected in 45 unique genes. The most frequently mutated genes were TP53 (7), RUNX1 (6), WT1 (4), MLL2 (3), FLT3 (3), CBL (2), ASXL1 (2), TET2 (2), MAP3K6 (2), MLL (2), and MAP3K1 (2). Targetable or potentially targetable biomarkers were found in 56% of cases. Overall survival was 19.5 months (range = 0–70 m). Ten patients were treated with an allogeneic stem cell transplant and had superior outcome (p = 0.0013). In one the largest series of MPAL cases to date, we corroborate previous findings with enriched detection of RUNX1 and FLT3–ITD mutations along with discovery of unreported mutations (MAP3K) that may be amenable to therapeutic manipulation. We also report the frequent occurrence of AML with MDS-related changes (AML-MRC)-defining cytogenetic abnormalities (26%). Finally, we show that those patients that received stem cell transplant had a better overall survival. Our findings support the need to genomically profile MPAL cases to exploit opportunities for targeted therapies in this orphan disease with dismal prognosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lymphomas and Leukemia)

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22 pages, 12454 KiB

Open AccessArticle

5-Demethylnobiletin Inhibits Cell Proliferation, Downregulates ID1 Expression, Modulates the NF-κB/TNF-α Pathway and Exerts Antileukemic Effects in AML Cells

by Pei-Yi Chen, Chih-Yang Wang, En-Ci Tsao, Yu-Ting Chen, Ming-Jiuan Wu, Chi-Tang Ho and Jui-Hung Yen

Int. J. Mol. Sci. 2022, 23(13), 7392; https://doi.org/10.3390/ijms23137392 - 2 Jul 2022

Cited by 7 | Viewed by 2787

Abstract

Acute myeloid leukemia (AML) is characterized by the dysregulation of hematopoietic cell proliferation, resulting in the accumulation of immature myeloid cells in bone marrow. 5-Demethylnobiletin (5-demethyl NOB), a citrus 5-hydroxylated polymethoxyflavone, has been reported to exhibit various bioactivities, such as antioxidant, anti-inflammatory and anticancer properties. In this study, we investigated the antileukemic effects of 5-demethyl NOB and its underlying molecular mechanisms in human AML cells. We found that 5-demethyl NOB (20–80 μM) significantly reduced human leukemia cell viability, and the following trend of effectiveness was observed: THP-1 ≈ U-937 > HEL > HL-60 > K562 cells. 5-Demethyl NOB (20 and 40 μM) modulated the cell cycle through the regulation of p21, cyclin E1 and cyclin A1 expression and induced S phase arrest. 5-Demethyl NOB also promoted leukemia cell apoptosis and differentiation. Microarray-based transcriptome, Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA) of differentially expressed genes (DEGs) analysis showed that the expression of inhibitor of differentiation/DNA binding 1 (ID1), a gene associated with the GO biological process (BP) cell population proliferation (GO: 0008283), was most strongly suppressed by 5-demethyl NOB (40 μM) in THP-1 cells. We further demonstrated that 5-demethyl NOB-induced ID1 reduction was associated with the inhibition of leukemia cell growth. Moreover, DEGs involved in the hallmark gene set NF-κB/TNF-α signaling pathway were markedly enriched and downregulated by 5-demethyl NOB. Finally, we demonstrated that 5-demethyl NOB (20 and 40 μM), combined with cytarabine, synergistically reduced THP-1 and U-937 cell viability. Our current findings support that 5-demethyl NOB dramatically suppresses leukemia cell proliferation and may serve as a potential phytochemical for human AML chemotherapy. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lymphomas and Leukemia)

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Review

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15 pages, 703 KiB

Open AccessReview

The Emerging Role of Venetoclax-Based Treatments in Acute Lymphoblastic Leukemia

by Shlomzion Aumann, Adir Shaulov, Arnon Haran, Noa Gross Even-Zohar, Vladimir Vainstein and Boaz Nachmias

Int. J. Mol. Sci. 2022, 23(18), 10957; https://doi.org/10.3390/ijms231810957 - 19 Sep 2022

Cited by 21 | Viewed by 4609

Abstract

Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a growing number of publications bring forth the use of venetoclax in patients with acute lymphoblastic leukemia (ALL). In the current review, we present the biological rationale of BCL-2 inhibition in ALL, how the interplay of BH3 proteins modulate the response and the current clinical experience with various combinations. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lymphomas and Leukemia)

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13 pages, 2478 KiB

Open AccessCase Report

Successful Treatment of Large B-Cell Lymphoma in a Child with Compound Heterozygous Mutation in the ATM Gene

by Jakub Czarny, Marta Andrzejewska, Olga Zając-Spychała, Elżbieta Latos-Grażyńska, Agata Pastorczak, Kamila Wypyszczak, Aleksandra Szczawińska-Popłonyk, Izabela Niewiadomska-Wojnałowicz, Agnieszka Wziątek, Patrycja Marciniak-Stępak, Michał Dopierała, Jadwiga Małdyk, Katarzyna Jończyk-Potoczna and Katarzyna Derwich

Int. J. Mol. Sci. 2023, 24(2), 1099; https://doi.org/10.3390/ijms24021099 - 6 Jan 2023

Cited by 4 | Viewed by 2752

Abstract

Ataxia-telangiectasia (AT) is a multisystemic neurodegenerative inborn error of immunity (IEI) characterized by DNA repair defect, chromosomal instability, and hypersensitivity to ionizing radiation. Impaired DNA double-strand break repair determines a high risk of developing hematological malignancies, especially lymphoproliferative diseases. Poor response to treatment, excessive chemotherapy toxicities, and the need for avoiding exposure to ionizing radiation make the successful clinical management of patients with AT challenging for oncologists. We describe the favorable outcome of the LBCL with IRF4 rearrangement at stage III in a 7-year-old female patient diagnosed with AT. The patient was treated according to the B-HR arm of the INTER-B-NHL-COP 2010 protocol, including the administration of rituximab, cyclophosphamide, methotrexate, prednisone, etc. She presented excessive treatment toxicities despite individually reduced doses of methotrexate and cyclophosphamide. However, in the MRI there was no significant reduction in pathologic lymph nodes after three immunochemotherapy courses. Therefore, a lymph node biopsy was taken. Its subsequent histopathological examination revealed tuberculosis-like changes, though tuberculosis suspicion was excluded. After two following immunochemotherapy courses, PET-CT confirmed complete remission. From March 2022 onwards, the patient has remained in remission under the care of the outpatient children’s oncology clinic. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lymphomas and Leukemia)

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