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Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition
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Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition

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 November 2025 | Viewed by 3180

Special Issue Editor

Dr. Stella Bouziana

E-Mail Website
Guest Editor
Department of Haematology, King's College Hospital, London WC2R 2LS, 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.

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Keywords

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

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Published Papers (4 papers)

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Research

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13 pages, 860 KiB  
Article
Identification of Genetic Variants Using Next-Generation Sequencing in Pediatric Myelodysplastic Syndrome: From Disease Biology to Clinical Applications
by Viviane Lamim Lovatel, Gerson Moura Ferreira, Beatriz Ferreira da Silva, Rayane de Souza Torres, Rita de Cássia Barbosa da Silva Tavares, Ana Paula Silva Bueno, Eliana Abdelhay and Teresa de Souza Fernandez
Int. J. Mol. Sci. 2025, 26(14), 6907; https://doi.org/10.3390/ijms26146907 - 18 Jul 2025
Viewed by 176
Abstract
This study aimed to identify genetic variants using a customized next-generation sequencing (NGS) panel for pediatric myelodysplastic syndrome (pMDS) and to explore their associations with cytogenetic and clinical characteristics. Cytogenetic analyses were conducted using G-banding and fluorescence in situ hybridization. NGS was performed [...] Read more.
This study aimed to identify genetic variants using a customized next-generation sequencing (NGS) panel for pediatric myelodysplastic syndrome (pMDS) and to explore their associations with cytogenetic and clinical characteristics. Cytogenetic analyses were conducted using G-banding and fluorescence in situ hybridization. NGS was performed with the Ion Torrent Personal Genome Machine for the following genes: GATA2, RUNX1, CEBPA, ANKRD26, ETV6, SAMD9, SAMD9L, PTPN11, NRAS, SETBP1, DDX41, TP53, FLT3, SRP72, and JAK3. Analyses were performed with Ion Reporter 5.20.8.0 software. Genetic variants were classified using the dbSNP, 1000 Genomes, COSMIC, and Varsome databases. We analyzed 25 cases of pMDS; 15 presented abnormal karyotypes, and 19 showed genetic variants. Among the 29 variants identified across 12/15 genes, 27% were pathogenic and 14% were likely pathogenic, with NRAS and GATA2 most frequently associated with disease progression. A new somatic variant of uncertain significance in SETBP1 was detected in seven patients showing heterogeneous clinical outcomes. Genetic variants were found in 7/10 patients with normal karyotypes, indicating that submicroscopic alterations can shed light on disease biology. Our results highlight the critical role of a targeted NGS panel in identifying molecular alterations associated with pMDS pathogenesis, thereby enhancing diagnostic precision, prognosis, and aiding in treatment selection. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)
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21 pages, 5292 KiB  
Article
Downregulation of S6 Kinase and Hedgehog–Gli1 by Inhibition of Fatty Acid Synthase in AML with FLT3-ITD Mutation
by Maxim Kebenko, Ruimeng Zhuang, Konstantin Hoffer, Anna Worthmann, Stefan Horn, Malte Kriegs, Jan Vorwerk, Nikolas von Bubnoff, Cyrus Khandanpour, Niklas Gebauer, Sivahari Prasad Gorantla, Walter Fiedler, Carsten Bokemeyer and Manfred Jücker
Int. J. Mol. Sci. 2025, 26(12), 5721; https://doi.org/10.3390/ijms26125721 - 14 Jun 2025
Viewed by 528
Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase [...] Read more.
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog–Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog–Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)
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20 pages, 5060 KiB  
Article
Acquired Resistance to Decitabine Associated with the Deoxycytidine Kinase A180P Mutation: Implications for the Order of Hypomethylating Agents in Myeloid Malignancies Treatment
by Kristina Simonicova, Lubos Janotka, Helena Kavcova, Ivana Borovska, Zdena Sulova, Albert Breier and Lucia Messingerova
Int. J. Mol. Sci. 2025, 26(11), 5083; https://doi.org/10.3390/ijms26115083 - 25 May 2025
Viewed by 528
Abstract
The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2’-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid [...] Read more.
The backbone of therapy for elderly patients with myelodysplastic syndromes and acute myeloid leukemia consists of hypomethylating agents 5-aza-2’-deoxycytidine (DAC) and 5-azacytidine (AZA). However, resistance frequently emerges during treatment. To investigate the mechanisms of resistance, we generated DAC-resistant variants of the acute myeloid leukemia cell lines, MOLM-13 and SKM-1, through their prolonged cultivation in increasing concentrations of DAC. The resistant cell variants, MOLM-13/DAC and SKM-1/DAC, exhibited cross-resistance to cytarabine and gemcitabine, but remained sensitive to AZA. Existing studies have suggested that the loss of deoxycytidine kinase (DCK) may play an important role in DAC resistance. DCK is critical for DAC activation, but the precise mechanisms of its downregulation remain incompletely understood. We identified a novel point mutation (A180P) in DCK, which results in acquired DAC resistance. Although the DCK mRNA was actively transcribed, the mutant protein was not detected in DAC-resistant cells. The transfection of HEK293 cells with the mutant DCK, combined with proteasomal inhibition, revealed rapid proteasomal degradation, establishing a mechanistic link between the A180P mutation and DCK loss, not previously described. This highlights the importance of also evaluating DCK at the protein and/or enzymatic activity levels in patients. The loss of functional DCK impairs the phosphorylation of deoxynucleosides, conferring resistance to DAC, gemcitabine, and cytarabine, but AZA, phosphorylated by uridine–cytidine kinase, remains effective and may represent a therapeutic alternative for patients with acquired DAC resistance. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)
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Review

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29 pages, 2405 KiB  
Review
Tumor Microenvironment, Inflammation, and Inflammatory Prognostic Indices in Diffuse Large B-Cell Lymphomas: A Narrative Review
by Zorica Cvetković, Olivera Marković, Gligorije Marinković, Snežana Pejić and Vesna Vučić
Int. J. Mol. Sci. 2025, 26(12), 5670; https://doi.org/10.3390/ijms26125670 - 13 Jun 2025
Viewed by 1029
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, characterized by significant variability in clinical outcomes. Emerging evidence highlights the pivotal role of inflammation in the pathogenesis and prognosis of DLBCL. This narrative review explores the interplay between the [...] Read more.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, characterized by significant variability in clinical outcomes. Emerging evidence highlights the pivotal role of inflammation in the pathogenesis and prognosis of DLBCL. This narrative review explores the interplay between the tumor microenvironment, inflammatory processes, and prognostic indices used in DLBCL, focusing on biomarkers, immune responses, and systemic inflammation. These indices show promise as predictive and prognostic tools comparable to molecular markers, such as gene expression profiling, which are currently considered gold standards in prognosis but are often costly and technically demanding. By synthesizing findings from the current literature, this article highlights the potential of inflammatory indices as accessible and cost-effective prognostic alternatives to molecular markers in DLBCL, while also underscoring the need for further research to validate their clinical utility. Full article
(This article belongs to the Special Issue Hematological Malignancies: Molecular Mechanisms and Therapy, 2nd Edition)
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