Molecular Mechanisms of Hematological Malignancies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 19043

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Guest Editor
Department of Medicine, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
Interests: acute myeloid leukemia; cell biology; metabolism; molecular biology; genetics; gene editing
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Special Issue Information

Dear Colleagues,

Hematological malignancies comprise a group of serious diseases of the blood-forming organ system. Overall, hematological diseases account for about 7% of all malignant diseases and can be divided into leukemias, malignant lymphomas, myeloproliferative diseases and myelodysplastic syndromes. The causes as well as the prognosis of these diseases are highly variable. Whereas some of these diseases are treatable and often curable (e.g., ALL or Hodgkin's lymphoma), other diseases are not permanently controllable and ultimately lead to the patient’s death (e.g., AML and multiple myeloma). This Special Issue will focus on findings elucidating the molecular mechanisms of the development, maintenance and drug evasion of these diseases. We therefore invite submissions of original data or review articles with the aim of making these findings available to the scientific audience in an easily digestible form.

Dr. Frank Schnütgen
Guest Editor

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Keywords

  • hematopoiesis
  • cancer
  • leukemia
  • molecular mechanism
  • oncogenic signaling

Published Papers (7 papers)

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Research

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20 pages, 2252 KiB  
Article
Pharmacogenomic Analyses Implicate B Cell Developmental Status and MKL1 as Determinants of Sensitivity toward Anti-CD20 Monoclonal Antibody Therapy
by George W. Small, Farida S. Akhtari, Adrian J. Green, Tammy M. Havener, Michael Sikes, Julia Quintanhila, Ricardo D. Gonzalez, David M. Reif, Alison A. Motsinger-Reif, Howard L. McLeod and Tim Wiltshire
Cells 2023, 12(12), 1574; https://doi.org/10.3390/cells12121574 - 07 Jun 2023
Viewed by 1399
Abstract
Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of [...] Read more.
Monoclonal antibody (mAb) therapy directed against CD20 is an important tool in the treatment of B cell disorders. However, variable patient response and acquired resistance remain important clinical challenges. To identify genetic factors that may influence sensitivity to treatment, the cytotoxic activity of three CD20 mAbs: rituximab; ofatumumab; and obinutuzumab, were screened in high-throughput assays using 680 ethnically diverse lymphoblastoid cell lines (LCLs) followed by a pharmacogenomic assessment. GWAS analysis identified several novel gene candidates. The most significant SNP, rs58600101, in the gene MKL1 displayed ethnic stratification, with the variant being significantly more prevalent in the African cohort and resulting in reduced transcript levels as measured by qPCR. Functional validation of MKL1 by shRNA-mediated knockdown of MKL1 resulted in a more resistant phenotype. Gene expression analysis identified the developmentally associated TGFB1I1 as the most significant gene associated with sensitivity. qPCR among a panel of sensitive and resistant LCLs revealed immunoglobulin class-switching as well as differences in the expression of B cell activation markers. Flow cytometry showed heterogeneity within some cell lines relative to surface Ig isotype with a shift to more IgG+ cells among the resistant lines. Pretreatment with prednisolone could partly reverse the resistant phenotype. Results suggest that the efficacy of anti-CD20 mAb therapy may be influenced by B cell developmental status as well as polymorphism in the MKL1 gene. A clinical benefit may be achieved by pretreatment with corticosteroids such as prednisolone followed by mAb therapy. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hematological Malignancies)
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16 pages, 2999 KiB  
Article
The TT Genotype of the KIAA1524 rs2278911 Polymorphism Is Associated with Poor Prognosis in Multiple Myeloma
by Aneta Szudy-Szczyrek, Radosław Mlak, Marcin Mazurek, Tomasz Krajka, Sylwia Chocholska, Paulina Bitkowska, Marta Jutrzenka, Michał Szczyrek, Iwona Homa-Mlak, Andrzej Krajka, Teresa Małecka-Massalska and Marek Hus
Cells 2023, 12(7), 1029; https://doi.org/10.3390/cells12071029 - 28 Mar 2023
Cited by 1 | Viewed by 1451
Abstract
Background: The KIAA1524 gene encodes an oncoprotein, CIP2A, which inhibits the phosphorylation of the Akt kinase B, stabilizes the c-Myc protein, and, through that, promotes cancerogenesis. An increase in CIP2A expression has been observed in numerous solid tumors and hematologic malignancies, including multiple [...] Read more.
Background: The KIAA1524 gene encodes an oncoprotein, CIP2A, which inhibits the phosphorylation of the Akt kinase B, stabilizes the c-Myc protein, and, through that, promotes cancerogenesis. An increase in CIP2A expression has been observed in numerous solid tumors and hematologic malignancies, including multiple myeloma (MM). The aim of our study was to evaluate the clinical impact of the functional single nucleotide polymorphisms (SNP) of the KIAA1524 gene (rs2278911, 686C > T) in MM patients. Methods: The study group consisted of 128 patients with de novo MM. EDTA venous blood samples were collected prior to the treatment. The SNPs were analyzed by Real-Time PCR with the use of specific Taqman probes. Results: Multivariable analysis revealed that variables independently associated with shorter progression-free survival (PFS) included thrombocytopenia, delTP53 and IGH/CCND1 translocation and the TT genotype of the KIAA1524 gene (686C > T) (median PFS: 6 vs. 25 months; HR = 7.18). On the other hand, autologous haematopoietic stem cell transplantation (AHSCT) was related to a lower risk of early disease progression. Moreover, light chain disease, International Staging System (ISS) 3, poor performance status, hypoalbuminemia, IGH/FGFR3 translocation and the TT genotype of the KIAA1524 gene (686C > T) were independent prognostic factors associated with shorter overall survival (OS) (median OS: 8 vs. 45 months; HR = 7.08). Conclusion: The evaluation of the SNP 686C > T of the KIAA1524 gene could be used as a diagnostic tool in MM patients at risk of early disease progression and death. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hematological Malignancies)
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19 pages, 2908 KiB  
Article
Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma
by Yasmeen Niazi, Nagarajan Paramasivam, Joanna Blocka, Abhishek Kumar, Stefanie Huhn, Matthias Schlesner, Niels Weinhold, Rolf Sijmons, Mirjam De Jong, Brian Durie, Hartmut Goldschmidt, Kari Hemminki and Asta Försti
Cells 2023, 12(1), 96; https://doi.org/10.3390/cells12010096 - 26 Dec 2022
Cited by 2 | Viewed by 1741
Abstract
Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about [...] Read more.
Multiple myeloma (MM) is a plasma cell malignancy whereby a single clone of plasma cells over-propagates in the bone marrow, resulting in the increased production of monoclonal immunoglobulin. While the complex genetic architecture of MM is well characterized, much less is known about germline variants predisposing to MM. Genome-wide sequencing approaches in MM families have started to identify rare high-penetrance coding risk alleles. In addition, genome-wide association studies have discovered several common low-penetrance risk alleles, which are mainly located in the non-coding genome. Here, we further explored the genetic basis in familial MM within the non-coding genome in whole-genome sequencing data. We prioritized and characterized 150 upstream, 5′ untranslated region (UTR) and 3′ UTR variants from 14 MM families, including 20 top-scoring variants. These variants confirmed previously implicated biological pathways in MM development. Most importantly, protein network and pathway enrichment analyses also identified 10 genes involved in mitogen-activated protein kinase (MAPK) signaling pathways, which have previously been established as important MM pathways. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hematological Malignancies)
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Review

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17 pages, 837 KiB  
Review
Molecular Drivers of Myelodysplastic Neoplasms (MDS)—Classification and Prognostic Relevance
by Fieke W. Hoff and Yazan F. Madanat
Cells 2023, 12(4), 627; https://doi.org/10.3390/cells12040627 - 15 Feb 2023
Cited by 2 | Viewed by 2411
Abstract
Myelodysplastic neoplasms (MDS) form a broad spectrum of clonal myeloid malignancies arising from hematopoietic stem cells that are characterized by progressive and refractory cytopenia and morphological dysplasia. Recent advances in unraveling the underlying pathogenesis of MDS have led to the identification of molecular [...] Read more.
Myelodysplastic neoplasms (MDS) form a broad spectrum of clonal myeloid malignancies arising from hematopoietic stem cells that are characterized by progressive and refractory cytopenia and morphological dysplasia. Recent advances in unraveling the underlying pathogenesis of MDS have led to the identification of molecular drivers and secondary genetic events. With the overall goal of classifying patients into relevant disease entities that can aid to predict clinical outcomes and make therapeutic decisions, several MDS classification models (e.g., French–American–British, World Health Organization, and International Consensus Classification) as well as prognostication models (e.g., International Prognostic Scoring system (IPSS), the revised IPSS (IPSS-R), and the molecular IPSS (IPSS-M)), have been developed. The IPSS-M is the first model that incorporates molecular data for individual genes and facilitates better prediction of clinical outcome parameters compared to older versions of this model (i.e., overall survival, disease progression, and leukemia-free survival). Comprehensive classification and accurate risk prediction largely depend on the integration of genetic mutations that drive the disease, which is crucial to improve the diagnostic work-up, guide treatment decision making, and direct novel therapeutic options. In this review, we summarize the most common cytogenetic and genomic drivers of MDS and how they impact MDS prognosis and treatment decisions. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hematological Malignancies)
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15 pages, 806 KiB  
Review
Novel Molecular Therapies and Genetic Landscape in Selected Rare Diseases with Hematologic Manifestations: A Review of the Literature
by Gabriela Ręka, Martyna Stefaniak and Monika Lejman
Cells 2023, 12(3), 449; https://doi.org/10.3390/cells12030449 - 30 Jan 2023
Viewed by 2703
Abstract
Rare diseases affect less than 1 in 2000 people and are characterized by a serious, chronic, and progressive course. Among the described diseases, a mutation in a single gene caused mastocytosis, thrombotic thrombocytopenic purpura, Gaucher disease, and paroxysmal nocturnal hemoglobinuria (KIT, [...] Read more.
Rare diseases affect less than 1 in 2000 people and are characterized by a serious, chronic, and progressive course. Among the described diseases, a mutation in a single gene caused mastocytosis, thrombotic thrombocytopenic purpura, Gaucher disease, and paroxysmal nocturnal hemoglobinuria (KIT, ADAMTS13, GBA1, and PIG-A genes, respectively). In Castleman disease, improper ETS1, PTPN6, TGFBR2, DNMT3A, and PDGFRB genes cause the appearance of symptoms. In histiocytosis, several mutation variants are described: BRAF, MAP2K1, MAP3K1, ARAF, ERBB3, NRAS, KRAS, PICK1, PIK3R2, and PIK3CA. Genes like HPLH1, PRF1, UNC13D, STX11, STXBP2, SH2D1A, BIRC4, ITK, CD27, MAGT1, LYST, AP3B1, and RAB27A are possible reasons for hemophagocytic lymphohistiocytosis. Among novel molecular medicines, tyrosine kinase inhibitors, mTOR inhibitors, BRAF inhibitors, interleukin 1 or 6 receptor antagonists, monoclonal antibodies, and JAK inhibitors are examples of drugs expanding therapeutic possibilities. An explanation of the molecular basis of rare diseases might lead to a better understanding of the pathogenesis and prognosis of the disease and may allow for the development of new molecularly targeted therapies. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hematological Malignancies)
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21 pages, 1752 KiB  
Review
The Landscape of Secondary Genetic Rearrangements in Pediatric Patients with B-Cell Acute Lymphoblastic Leukemia with t(12;21)
by Agnieszka Kaczmarska, Justyna Derebas, Michalina Pinkosz, Maciej Niedźwiecki and Monika Lejman
Cells 2023, 12(3), 357; https://doi.org/10.3390/cells12030357 - 18 Jan 2023
Cited by 3 | Viewed by 3841
Abstract
The most frequent chromosomal rearrangement in childhood B-cell acute lymphoblastic leukemia (B-ALL) is translocation t(12;21)(p13;q22). It results in the fusion of the ETV6::RUNX1 gene, which is active in the regulation of multiple crucial cellular pathways. Recent studies hypothesize that many translocations are influenced [...] Read more.
The most frequent chromosomal rearrangement in childhood B-cell acute lymphoblastic leukemia (B-ALL) is translocation t(12;21)(p13;q22). It results in the fusion of the ETV6::RUNX1 gene, which is active in the regulation of multiple crucial cellular pathways. Recent studies hypothesize that many translocations are influenced by RAG-initiated deletions, as well as defects in the RAS and NRAS pathways. According to a “two-hit” model for the molecular pathogenesis of pediatric ETV6::RUNX1-positive B-ALL, the t(12;21) translocation requires leukemia-causing secondary mutations. Patients with ETV6::RUNX1 express up to 60 different aberrations, which highlights the heterogeneity of this B-ALL subtype and is reflected in differences in patient response to treatment and chances of relapse. Most studies of secondary genetic changes have concentrated on deletions of the normal, non-rearranged ETV6 allele. Other predominant structural changes included deletions of chromosomes 6q and 9p, loss of entire chromosomes X, 8, and 13, duplications of chromosome 4q, or trisomy of chromosomes 21 and 16, but the impact of these changes on overall survival remains unclarified. An equally genetically diverse group is the recently identified new B-ALL subtype ETV6::RUNX1-like ALL. In our review, we provide a comprehensive description of recurrent secondary mutations in pediatric B-ALL with t(12;21) to emphasize the value of investigating detailed molecular mechanisms in ETV6::RUNX1-positive B-ALL, both for our understanding of the etiology of the disease and for future clinical advances in patient treatment and management. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hematological Malignancies)
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16 pages, 337 KiB  
Review
Coming of Age for BTK Inhibitor Therapy: A Review of Zanubrutinib in Waldenström Macroglobulinemia
by Javier Muñoz, Jonas Paludo, Shayna Sarosiek and Jorge J. Castillo
Cells 2022, 11(20), 3287; https://doi.org/10.3390/cells11203287 - 19 Oct 2022
Cited by 4 | Viewed by 4535
Abstract
Waldenström macroglobulinemia (WM) is a rare form of non-Hodgkin B-cell lymphoma with a variable clinical presentation that can impact a patient’s quality of life by causing anemia, peripheral neuropathy, serum hyperviscosity, extramedullary disease, and other symptoms. There are several safe and effective treatment [...] Read more.
Waldenström macroglobulinemia (WM) is a rare form of non-Hodgkin B-cell lymphoma with a variable clinical presentation that can impact a patient’s quality of life by causing anemia, peripheral neuropathy, serum hyperviscosity, extramedullary disease, and other symptoms. There are several safe and effective treatment regimens for patients with WM, and the choice of therapy should be made in a personalized fashion considering the patient’s symptoms, comorbidities, and genomic profile. Bruton tyrosine kinase (BTK) inhibitors are a new option to treat patients with WM. Zanubrutinib is a next-generation covalent BTK inhibitor designed to have fewer off-target effects than previous BTK inhibitors. This review summarizes the pharmacokinetic and pharmacodynamic properties of zanubrutinib as well as safety and efficacy findings. Then, it explores the health economic and outcomes research associated with the costs of treating patients with WM and the reasons why zanubrutinib may be a more cost-effective treatment option compared with ibrutinib, a first-generation BTK inhibitor. Future directions for the treatment of WM focus on the use of zanubrutinib in combination therapy. Combinations based on effective ibrutinib or acalabrutinib treatments may be effectively applied with zanubrutinib given the similar mechanism of action for these BTK inhibitors. Combination therapies could also help prevent the development of disease resistance, minimize toxicity, and support treatment regimens of finite duration. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hematological Malignancies)
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