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Life
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Molecular Pathways in Hematologic Neoplasm
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Molecular Pathways in Hematologic Neoplasm

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Physiology and Pathology".

Deadline for manuscript submissions: closed (16 September 2022) | Viewed by 30301

Special Issue Editor

Dr. Katalin Kelemen

E-Mail Website
Guest Editor
Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ 85259, USA
Interests: bone marrow and lymph node pathology; flow cytometry; molecular pathways; lymphoma; leukemia

Special Issue Information

Dear Colleagues,

Historically, hematologic neoplasms played a major role in the advancement of our understanding of the genetic and molecular pathways of human cancer. Diagnostic classification of leukemias and lymphomas requires cytogenetic and molecular genetic information based on the current World Health Organization (WHO) Classification. Due to the easy accessibility of peripheral blood and bone marrow samples, leukemias and lymphomas continue to provide a hotbed for discovery.

Recently, the increased availability of advanced cytogenetic and molecular techniques, such as comparative genomic hybridization, next generation sequencing and gene expression profiling resulted in an outburst of the discovery of new molecular pathways in hematologic neoplasms. Consequently, every aspect of our approach to disease, including diagnosis, classification, treatment, and prognostic evaluation, has been reshaped. Within the spectrum of myeloid neoplasm, new molecular knowledge translated into entirely new disease categories, while certain mutations gained a role as diagnosis-defining markers, or markers of prognosis, guiding clinical decision making. Lymphoid neoplasms with heterogeneous outcomes became further classifiable by molecular analysis, and targeted therapies followed. New treatments targeting specific molecular pathways became introduced, and many others are currently under investigation by clinical trials.

In this Special Issue of Life, we invite researchers from all over the world to share advances in our understanding of molecular pathways in the pathogenesis and evolution of leukemias and lymphomas. We invite original work and review articles, dealing with new molecular techniques, signaling pathways, mechanisms of disease evolution, targetable molecular pathways, minimal residual disease detection, and models for predicting prognosis.

Dr. Katalin Kelemen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • leukemia
  • lymphoma
  • myeloid neoplasm
  • cytogenetics
  • molecular genetics
  • signal transduction
  • transcription regulation
  • mutation
  • targetable therapies
  • prognostic models
  • minimal residual disease

Published Papers (8 papers)

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Research

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13 pages, 1285 KiB  
Article
Tomentosin a Sesquiterpene Lactone Induces Antiproliferative and Proapoptotic Effects in Human Burkitt Lymphoma by Deregulation of Anti- and Pro-Apoptotic Genes
by Patrizia Virdis, Irene Marchesi, Francesco Paolo Fiorentino, Rossana Migheli, Luca Sanna, Valentina Bordoni, Giorgio Pintore, Grazia Galleri, Maria Rosaria Muroni, Luigi Bagella, Claudio Fozza, Maria Rosaria De Miglio and Luigi Podda
Life 2021, 11(11), 1128; https://doi.org/10.3390/life11111128 - 23 Oct 2021
Cited by 4 | Viewed by 2175
Abstract
(1) Tomentosin is the most representative sesquiterpene lactone extracted by I. viscosa. Recently, it has gained particular attention in therapeutic oncologic fields due to its anti-tumor properties. (2) In this study, the potential anticancer features of tomentosin were evaluated on human Burkitt’s lymphoma [...] Read more.
(1) Tomentosin is the most representative sesquiterpene lactone extracted by I. viscosa. Recently, it has gained particular attention in therapeutic oncologic fields due to its anti-tumor properties. (2) In this study, the potential anticancer features of tomentosin were evaluated on human Burkitt’s lymphoma (BL) cell line, treated with increasing tomentosin concentration for cytotoxicity screening. (3) Our data showed that both cell cycle arrest and cell apoptosis induction are responsible of the antiproliferative effects of tomentosin and may end in the inhibition of BL cell viability. Moreover, a microarray gene expression profile was performed to assess differentially expressed genes contributing to tomentosin activity. Seventy-five genes deregulated by tomentosin have been identified. Downregulated genes are enriched in immune-system pathways, and PI3K/AKT and JAK/STAT pathways which favor proliferation and growth processes. Importantly, different deregulated genes identified in tomentosin-treated BL cells are prevalent in molecular pathways known to lead to cellular death, specifically by apoptosis. Tomentosin-treatment in BL cells induces the downregulation of antiapoptotic genes such as BCL2A1 and CDKN1A and upregulation of the proapoptotic PMAIP1 gene. (4) Overall, our results suggest that tomentosin could be taken into consideration as a potential natural product with limited toxicity and relevant anti-tumoral activity in the therapeutic options available to BL patients. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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Review

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16 pages, 737 KiB  
Review
Molecular Pathways in Clonal Hematopoiesis: From the Acquisition of Somatic Mutations to Transformation into Hematologic Neoplasm
by Charles Gaulin, Katalin Kelemen and Cecilia Arana Yi
Life 2022, 12(8), 1135; https://doi.org/10.3390/life12081135 - 28 Jul 2022
Cited by 7 | Viewed by 6623
Abstract
Hematopoietic stem cell aging, through the acquisition of somatic mutations, gives rise to clonal hematopoiesis (CH). While a high prevalence of CH has been described in otherwise healthy older adults, CH confers an increased risk of both hematologic and non-hematologic diseases. Classification of [...] Read more.
Hematopoietic stem cell aging, through the acquisition of somatic mutations, gives rise to clonal hematopoiesis (CH). While a high prevalence of CH has been described in otherwise healthy older adults, CH confers an increased risk of both hematologic and non-hematologic diseases. Classification of CH into clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) further describes this neoplastic myeloid precursor state and stratifies individuals at risk of developing clinically significant complications. The sequential acquisition of driver mutations, such as DNMT3A, TET2, and ASXL1, provide a selective advantage and lead to clonal expansion. Inflammation, microbiome signatures, and external selective pressures also contribute to clonal evolution. Despite significant progress in recent years, the precise molecular mechanisms driving CH transformation to hematologic neoplasms are not well defined. Further understanding of these complex mechanisms may improve risk stratification and introduce therapeutic interventions in CH. Here we discuss the genetic drivers underpinning CH, mechanisms for clonal evolution, and transformation to hematologic neoplasm. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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12 pages, 789 KiB  
Review
Review of Multiple Myeloma Genetics including Effects on Prognosis, Response to Treatment, and Diagnostic Workup
by Julia Erin Wiedmeier-Nutor and Peter Leif Bergsagel
Life 2022, 12(6), 812; https://doi.org/10.3390/life12060812 - 30 May 2022
Cited by 9 | Viewed by 2627
Abstract
Multiple myeloma is a disorder of the monoclonal plasma cells and is the second most common hematologic malignancy. Despite improvements in survival with newer treatment regimens, multiple myeloma remains an incurable disease and most patients experience multiple relapses. Multiple myeloma disease initiation and [...] Read more.
Multiple myeloma is a disorder of the monoclonal plasma cells and is the second most common hematologic malignancy. Despite improvements in survival with newer treatment regimens, multiple myeloma remains an incurable disease and most patients experience multiple relapses. Multiple myeloma disease initiation and progression are highly dependent on complex genetic aberrations. This review will summarize the current knowledge of these genetic aberrations, how they affect prognosis and the response to treatment, and review sensitive molecular techniques for multiple myeloma workup, with the ultimate goal of detecting myeloma progression early, allowing for timely treatment initiation. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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22 pages, 746 KiB  
Review
Genetic Landscape of Peripheral T-Cell Lymphoma
by Vivian Hathuc and Friederike Kreisel
Life 2022, 12(3), 410; https://doi.org/10.3390/life12030410 - 11 Mar 2022
Cited by 7 | Viewed by 4452
Abstract
Peripheral T-Cell lymphoma (PTCL) comprises a heterogenous group of uncommon lymphomas derived from mature, post-thymic or “peripheral” T- and natural killer cells. The World Health Organization (WHO) emphasizes a multiparameter approach in the diagnosis and subclassification of these neoplasms, integrating clinical, morphologic, immunophenotypic, [...] Read more.
Peripheral T-Cell lymphoma (PTCL) comprises a heterogenous group of uncommon lymphomas derived from mature, post-thymic or “peripheral” T- and natural killer cells. The World Health Organization (WHO) emphasizes a multiparameter approach in the diagnosis and subclassification of these neoplasms, integrating clinical, morphologic, immunophenotypic, and genetic features into the final diagnosis. Clinical presentation is particularly important due to histologic, immunophenotypic and genetic variations within established subtypes, and no convenient immunophenotypic marker of monoclonality exists. In recent years, widespread use of gene expression profiling and next-generation sequencing (NGS) techniques have contributed to an improved understanding of the pathobiology in PTCLs, and these have been incorporated into the 2016 revised WHO classification of mature T- and NK-cell neoplasms which now encompasses nearly 30 distinct entities. This review discusses the genetic landscape of PTCL and its role in subclassification, prognosis, and potential targeted therapy. In addition to discussing T-Cell lymphoma subtypes with relatively well-defined or relevant genetic aberrancies, special attention is given to genetic advances in T-Cell lymphomas of T follicular helper cell (TFH) origin, highlighting genetic overlaps between angioimmunoblastic T-Cell lymphoma (AITL), follicular T-Cell lymphoma, and nodal peripheral T-Cell lymphoma with a TFH phenotype. Furthermore, genetic drivers will be discussed for ALK-negative anaplastic large cell lymphomas and their role in differentiating these from CD30+ peripheral T-Cell lymphoma, not otherwise specified (NOS) and primary cutaneous anaplastic large cell lymphoma. Lastly, a closer look is given to genetic pathways in peripheral T-Cell lymphoma, NOS, which may guide in teasing out more specific entities in a group of T-Cell lymphomas that represents the most common subcategory and is sometimes referred to as a “wastebasket” category. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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17 pages, 1277 KiB  
Review
Druggable Molecular Pathways in Chronic Lymphocytic Leukemia
by Mohammad Almasri, Marah Amer, Joseph Ghanej, Abdurraouf Mokhtar Mahmoud, Gianluca Gaidano and Riccardo Moia
Life 2022, 12(2), 283; https://doi.org/10.3390/life12020283 - 14 Feb 2022
Cited by 4 | Viewed by 3851
Abstract
Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is characterized by a high degree of clinical heterogeneity that is influenced by the disease’s molecular complexity. The genes most frequently affected in CLL cluster into specific biological pathways, including B-cell [...] Read more.
Chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is characterized by a high degree of clinical heterogeneity that is influenced by the disease’s molecular complexity. The genes most frequently affected in CLL cluster into specific biological pathways, including B-cell receptor (BCR) signaling, apoptosis, NF-κB, and NOTCH1 signaling. BCR signaling and the apoptosis pathway have been exploited to design targeted medicines for CLL therapy. Consistently, molecules that selectively inhibit specific BCR components, namely Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) as well as inhibitors of BCL2, have revolutionized the therapeutic management of CLL patients. Several BTK inhibitors and PI3K inhibitors with different modes of action are currently used or are in development in advanced stage clinical trials. Moreover, the restoration of apoptosis by the BCL2 inhibitor venetoclax offers meaningful clinical activity with a fixed-duration scheme. Inhibitors of the BCR and of BCL2 are able to overcome the chemorefractoriness associated with high-risk genetic features, including TP53 disruption. Other signaling cascades involved in CLL pathogenesis, in particular NOTCH signaling and NF-kB signaling, already provide biomarkers for a precision medicine approach to CLL and may represent potential druggable targets for the future. The aim of the present review is to discuss the druggable pathways of CLL and to provide the biological background of the high efficacy of targeted biological drugs in CLL. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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15 pages, 1711 KiB  
Review
The Role of Nucleophosmin 1 (NPM1) Mutation in the Diagnosis and Management of Myeloid Neoplasms
by Katalin Kelemen
Life 2022, 12(1), 109; https://doi.org/10.3390/life12010109 - 13 Jan 2022
Cited by 6 | Viewed by 3752
Abstract
Nucleophosmin (NPM1) is a multifunctional protein with both proliferative and growth-suppressive roles in the cell. In humans, NPM1 is involved in tumorigenesis via chromosomal translocations, deletions, or mutation. Acute myeloid leukemia (AML) with mutated NPM1, a distinct diagnostic entity by the current [...] Read more.
Nucleophosmin (NPM1) is a multifunctional protein with both proliferative and growth-suppressive roles in the cell. In humans, NPM1 is involved in tumorigenesis via chromosomal translocations, deletions, or mutation. Acute myeloid leukemia (AML) with mutated NPM1, a distinct diagnostic entity by the current WHO Classification of myeloid neoplasm, represents the most common diagnostic subtype in AML and is associated with a favorable prognosis. The persistence of NPM1 mutation in AML at relapse makes this mutation an ideal target for minimal measurable disease (MRD) detection. The clinical implication of this is far-reaching because NPM1-mutated AML is currently classified as being of standard risk, with the best treatment strategy (transplantation versus chemotherapy) yet undefined. Myeloid neoplasms with NPM1 mutations and <20% blasts are characterized by an aggressive clinical course and a rapid progression to AML. The pathological classification of these cases remains controversial. Future studies will determine whether NPM1 gene mutation may be sufficient for diagnosing NPM1-mutated AML independent of the blast count. This review aims to summarize the role of NPM1 in normal cells and in human cancer and discusses its current role in clinical management of AML and related myeloid neoplasms. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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13 pages, 591 KiB  
Review
Molecular Pathogenesis in Myeloid Neoplasms with Germline Predisposition
by Juehua Gao, Yihua Chen and Madina Sukhanova
Life 2022, 12(1), 46; https://doi.org/10.3390/life12010046 - 29 Dec 2021
Cited by 4 | Viewed by 2052
Abstract
Myeloid neoplasms with germline predisposition have recently been added as distinct provisional entities in the 2017 revision of the World Health Organization’s classification of tumors of hematopoietic and lymphatic tissue. Individuals with germline predisposition have increased risk of developing myeloid neoplasms—mainly acute myeloid [...] Read more.
Myeloid neoplasms with germline predisposition have recently been added as distinct provisional entities in the 2017 revision of the World Health Organization’s classification of tumors of hematopoietic and lymphatic tissue. Individuals with germline predisposition have increased risk of developing myeloid neoplasms—mainly acute myeloid leukemia and myelodysplastic syndrome. Although the incidence of myeloid neoplasms with germline predisposition remains poorly defined, these cases provide unique and important insights into the biology and molecular mechanisms of myeloid neoplasms. Knowledge of the regulation of the germline genes and their interactions with other genes, proteins, and the environment, the penetrance and clinical presentation of inherited mutations, and the longitudinal dynamics during the process of disease progression offer models and tools that can further our understanding of myeloid neoplasms. This knowledge will eventually translate to improved disease sub-classification, risk assessment, and development of more effective therapy. In this review, we will use examples of these disorders to illustrate the key molecular pathways of myeloid neoplasms. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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22 pages, 1129 KiB  
Review
Genetic Landscape of Myeloproliferative Neoplasms with an Emphasis on Molecular Diagnostic Laboratory Testing
by Arti Easwar and Alexa J. Siddon
Life 2021, 11(11), 1158; https://doi.org/10.3390/life11111158 - 30 Oct 2021
Cited by 8 | Viewed by 3068
Abstract
Chronic myeloproliferative neoplasms (MPNs) are hematopoietic stem cell neoplasms with driver events including the BCR-ABL1 translocation leading to a diagnosis of chronic myeloid leukemia (CML), or somatic mutations in JAK2, CALR, or MPL resulting in Philadelphia-chromosome-negative MPNs with constitutive activation of [...] Read more.
Chronic myeloproliferative neoplasms (MPNs) are hematopoietic stem cell neoplasms with driver events including the BCR-ABL1 translocation leading to a diagnosis of chronic myeloid leukemia (CML), or somatic mutations in JAK2, CALR, or MPL resulting in Philadelphia-chromosome-negative MPNs with constitutive activation of the JAK-STAT signaling pathway. In the Philadelphia-chromosome-negative MPNs, modern sequencing panels have identified a vast molecular landscape including additional mutations in genes involved in splicing, signal transduction, DNA methylation, and chromatin modification such as ASXL1, SF3B1, SRSF2, and U2AF1. These additional mutations often influence prognosis in MPNs and therefore are increasingly important for risk stratification. This review focuses on the molecular alterations within the WHO classification of MPNs and laboratory testing used for diagnosis. Full article
(This article belongs to the Special Issue Molecular Pathways in Hematologic Neoplasm)
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