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Hematological Malignancies: Molecular Mechanisms and Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 August 2024 | Viewed by 3859

Special Issue Editor


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Guest Editor
Department of Haematology, King's College Hospital, London SE5 9RS, UK
Interests: hematological malignancies; cellular therapies; immunotherapies; CAR T-cell therapies; hematopoietic stem cell transplantation; plasma cell dyscrasias; acute leukemias
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hematological malignancies comprise a wide range of relatively rare cancers. Aggressive types of hematological malignancies entail devastating outcomes, and their treatment includes many challenges. In recent decades, the molecular and genetic investigation of the pathogenesis of hematological malignancies has resulted in unprecedented advances in the landscape of the therapeutics of hematological cancers. The advent of novel types of therapies, such as targeted therapies, immunotherapies and cellular therapies, has revolutionized the field of hemato-oncology, offering long-term remission or even curing patients with highly aggressive and refractory malignancies. However, despite this massive progress, there are still hematological malignancies that remain uncured, and significant research should be undertaken to unravel the key pathways towards treatment.

This Special Issue aims to collect the latest original and review articles on investigating the molecular, genetic and immunological pathways that contribute to the pathogenesis of hematological malignancies or can serve as predictive, preventive and prognostic disease markers. In addition, this Special Issue welcomes research and review articles covering cutting-edge knowledge on novel therapeutics of hematological malignancies.

Dr. Stella Bouziana
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • hematological malignancies
  • molecular pathways
  • genetics
  • immunopathogenesis
  • biomarkers
  • novel therapies

Published Papers (4 papers)

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Research

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20 pages, 4784 KiB  
Article
An Optimized Peptide Antagonist of CXCR4 Limits Survival of BCR–ABL1-Transformed Cells in Philadelphia-Chromosome-Positive B-Cell Acute Lymphoblastic Leukemia
by Johanna Pohl, Angela Litz, Omar El Ayoubi, Armando Rodríguez-Alfonso, Ludger Ständker, Mirja Harms, Jan Münch, Hassan Jumaa and Moumita Datta
Int. J. Mol. Sci. 2024, 25(15), 8306; https://doi.org/10.3390/ijms25158306 - 30 Jul 2024
Viewed by 183
Abstract
Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR–ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR–ABL1-transformed mouse pre-B [...] Read more.
Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by reciprocal chromosomal translocation between chromosome 9 and 22, leading to the expression of constitutively active oncogenic BCR–ABL1 fusion protein. CXC chemokine receptor 4 (CXCR4) is essential for the survival of BCR–ABL1-transformed mouse pre-B cells, as the deletion of CXCR4 induces death in these cells. To investigate whether CXCR4 inhibition also effectively blocks BCR–ABL1-transformed cell growth in vitro, in this study, we explored an array of peptide-based inhibitors of CXCR4. The inhibitors were optimized derivatives of EPI-X4, an endogenous peptide antagonist of CXCR4. We observed that among all the candidates, EPI-X4 JM#170 (referred to as JM#170) effectively induced cell death in BCR–ABL1-transformed mouse B cells but had little effect on untransformed wild-type B cells. Importantly, AMD3100, a small molecule inhibitor of CXCR4, did not show this effect. Treatment with JM#170 induced transient JNK phosphorylation in BCR–ABL1-transformed cells, which in turn activated the intrinsic apoptotic pathway by inducing cJun, Bim, and Bax gene expressions. Combinatorial treatment of JM#170 with ABL1 kinase inhibitor Imatinib exerted a stronger killing effect on BCR–ABL1-transformed cells even at a lower dose of Imatinib. Surprisingly, JM#170 actively killed Sup-B15 cells, a BCR–ABL1+ human ALL cell line, but had no effect on the BCR–ABL1 697 cell line. This suggests that the inhibitory effect of JM#170 is specific for BCR–ABL1+ ALL. Taken together, JM#170 emerges as a potent novel drug against Ph+ ALL. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy)
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18 pages, 3185 KiB  
Article
Metabolic Profiling as an Approach to Differentiate T-Cell Acute Lymphoblastic Leukemia Cell Lines Belonging to the Same Genetic Subgroup
by Husam B. R. Alabed, Roberto Maria Pellegrino, Sandra Buratta, Anair Graciela Lema Fernandez, Roberta La Starza, Lorena Urbanelli, Cristina Mecucci, Carla Emiliani and Paolo Gorello
Int. J. Mol. Sci. 2024, 25(7), 3921; https://doi.org/10.3390/ijms25073921 - 31 Mar 2024
Viewed by 995
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive tumor mainly affecting children and adolescents. It is driven by multiple genetic mutations that together define the leukemic phenotype. Interestingly, based on genetic alterations and/or deregulated expression, at least six genetic subgroups have been recognized. [...] Read more.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive tumor mainly affecting children and adolescents. It is driven by multiple genetic mutations that together define the leukemic phenotype. Interestingly, based on genetic alterations and/or deregulated expression, at least six genetic subgroups have been recognized. The TAL/LMO subgroup is one of the most represented genetic subgroups, characterizing 30–45% of pediatric T-ALL cases. The study of lipid and metabolic profiles is increasingly recognized as a valuable tool for comprehending the development and progression of tumors. In this study, metabolic and lipidomic analysis via LC/MS have been carried out on four T-ALL cell lines belonging to the TAL/LMO subgroup (Jurkat, Molt-4, Molt-16, and CCRF-CEM) to identify new potential metabolic biomarkers and to provide a subclassification of T-ALL cell lines belonging to the same subgroup. A total of 343 metabolites were annotated, including 126 polar metabolites and 217 lipid molecules. The statistical analysis, for both metabolic and lipid profiles, shows significant differences and similarities among the four cell lines. The Molt-4 cell line is the most distant cell line and CCRF-CEM shows a high activity in specific pathways when compared to the other cell lines, while Molt-16 and Jurkat show a similar metabolic profile. Additionally, this study highlighted the pathways that differ in each cell line and the possible enzymes involved using bioinformatic tools, capable of predicting the pathways involved by studying the differences in the metabolic profiles. This experiment offers an approach to differentiate T-ALL cell lines and could open the way to verify and confirm the obtained results directly in patients. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy)
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Review

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27 pages, 1356 KiB  
Review
Haploidentical HSCT in the Treatment of Pediatric Hematological Disorders
by Anna Marszołek, Maria Leśniak, Anna Sekunda, Aleksander Siwek, Zuzanna Skiba, Monika Lejman and Joanna Zawitkowska
Int. J. Mol. Sci. 2024, 25(12), 6380; https://doi.org/10.3390/ijms25126380 - 9 Jun 2024
Viewed by 835
Abstract
Allogeneic hematopoietic stem cell transplantation has become a treatment option for otherwise non-curative conditions, both malignant and benign, affecting children and adults. Nevertheless, the latest research has been focusing extensively on transplantation from related and unrelated haploidentical donors, suitable for patients requiring emergent [...] Read more.
Allogeneic hematopoietic stem cell transplantation has become a treatment option for otherwise non-curative conditions, both malignant and benign, affecting children and adults. Nevertheless, the latest research has been focusing extensively on transplantation from related and unrelated haploidentical donors, suitable for patients requiring emergent hematopoietic stem cell transplantation (HSCT) in the absence of an HLA-matched donor. Haploidentical HSCT (haplo-HSCT) can be an effective treatment for non-malignant pediatric disorders, such as primary immunodeficiencies or hemoglobinopathies, by enabling a much quicker selection of the appropriate donor for virtually all patients, low incidence of graft-versus-host disease (GVHD), and transplant-related mortality (TRM). Moreover, the outcomes of haplo-HSCT among children with hematological malignancies have improved radically. The most demanding tasks for clinicians are minimizing T-cell-mediated alloreactivity as well as early GVHD prevention. As a result, several T-cell depletion approaches, such as ex vivo T-cell depletion (TCD), and T-cell replete approaches, such as a combination of anti-thymocyte globulin (ATG), post-transplantation cyclophosphamide (PTCy), cyclosporine/tacrolimus, mycophenolate mofetil, or methotrexate, have been taken up. As more research is needed to establish the most beneficial form of therapy, haplo-HSCT is currently considered an alternative donor strategy for pediatric and adult patients with complications like viral and bacterial infections, invasive fungal disease, and GVHD. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy)
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Other

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9 pages, 4225 KiB  
Case Report
ETV6::ABL1-Positive Myeloid Neoplasm: A Case of a Durable Response to Imatinib Mesylate without Additional or Previous Treatment
by Maria Teresa Bochicchio, Giovanni Marconi, Carmen Baldazzi, Lorenza Bandini, Francesca Ruggieri, Alessandro Lucchesi, Claudio Agostinelli, Elena Sabattini, Agnese Orsatti, Anna Ferrari, Giorgia Capirossi, Chiara Servili, Andrea Ghelli Luserna di Rorà, Giovanni Martinelli, Giorgia Simonetti and Gianantonio Rosti
Int. J. Mol. Sci. 2024, 25(1), 118; https://doi.org/10.3390/ijms25010118 (registering DOI) - 21 Dec 2023
Cited by 1 | Viewed by 885
Abstract
ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive [...] Read more.
ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive activation of the partner genes. Here, we report the case of a 54-year-old woman with a cryptic insertion of the 3′ region of ABL1 in the ETV6 gene. The patient was first diagnosed with idiopathic hypereosinophilic syndrome, according to the clinical history, conventional cytogenetics, standard molecular analyses and pathologist description. Next generation sequencing of diagnosis samples unexpectedly detected both ETV6::ABL1 type A and B fusion transcripts, which were then confirmed by FISH. The diagnosis was Myeloid/Lymphoid neoplasm with ETV6::ABL1 fusion, and the patient received imatinib mesylate treatment. In a follow-up after more than one year, the patient still maintained the molecular and complete hematological responses. This case highlights the importance of timely and proper diagnostics and prompt tyrosine kinase inhibitor treatment. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy)
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