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Molecular Pathology and Novel Therapies of Leukemia and Lymphoma

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

Deadline for manuscript submissions: closed (30 January 2024) | Viewed by 4870

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Special Issue Editor

Prof. Dr. Spiro Mihaylov Konstantinov

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Guest Editor

Department of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria
Interests: leukemia; lymphoma; solid tumors; antineoplastic agents; cell death induction; signal transduction; predictive biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Hematology has constantly been advancing in parallel with pharmacological and technological achievements that have expanded our understanding of the phenotypic, genetic, and molecular complexity as well as extreme clinical and biological heterogeneity of malignant blood diseases. This has, in turn, allowed for the development of more effective and less toxic alternative therapeutic approaches directed against critical molecular pathways. The continuous and rather extensive influx of new information regarding the key features and underlying mechanisms of, as well as treatment options in, hematological neoplasms requires frequent updating of this topic. The primary objective of this Special Issue is to provide the specialists involved in the clinical management of and experimental research into hematological neoplastic diseases with comprehensive and concise information on some important theoretical and practical developments in their biology, clinical assessment, and new treatment options, as well as on some molecular mechanisms of their pathogenesis and their respective translations into novel therapies.

Prof. Dr. Spiro Mihaylov Konstantinov
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

leukemia and lymphoma
chromosomal aberrations and gene mutations
epigenetics and epigenetic agents
immunotherapy (e.g., biTEs, CAR-T)
target drugs (small-molecule inhibitors, therapeutic antibodies)
new drugs
drug resistance
predictive biomarkers
innovative drug delivery systems

Published Papers (4 papers)

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Research

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25 pages, 4816 KiB

Open AccessArticle

Duocarmycin SA Reduces Proliferation and Increases Apoptosis in Acute Myeloid Leukemia Cells In Vitro

by William A. Chen, Terry G. Williams, Leena So, Natalie Drew, Jie Fang, Pedro Ochoa, Nhi Nguyen, Yasmeen Jawhar, Jide Otiji, Penelope J. Duerksen-Hughes, Mark E. Reeves, Carlos A. Casiano, Hongjian Jin, Sinisa Dovat, Jun Yang, Kristopher E. Boyle and Olivia L. Francis-Boyle

Int. J. Mol. Sci. 2024, 25(8), 4342; https://doi.org/10.3390/ijms25084342 - 14 Apr 2024

Viewed by 910

Abstract

Acute myeloid leukemia (AML) is a hematological malignancy that is characterized by an expansion of immature myeloid precursors. Despite therapeutic advances, the prognosis of AML patients remains poor and there is a need for the evaluation of promising therapeutic candidates to treat the disease. The objective of this study was to evaluate the efficacy of duocarmycin Stable A (DSA) in AML cells in vitro. We hypothesized that DSA would induce DNA damage in the form of DNA double-strand breaks (DSBs) and exert cytotoxic effects on AML cells within the picomolar range. Human AML cell lines Molm-14 and HL-60 were used to perform 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT), DNA DSBs, cell cycle, 5-ethynyl-2-deoxyuridine (EdU), colony formation unit (CFU), Annexin V, RNA sequencing and other assays described in this study. Our results showed that DSA induced DNA DSBs, induced cell cycle arrest at the G2M phase, reduced proliferation and increased apoptosis in AML cells. Additionally, RNA sequencing results showed that DSA regulates genes that are associated with cellular processes such as DNA repair, G2M checkpoint and apoptosis. These results suggest that DSA is efficacious in AML cells and is therefore a promising potential therapeutic candidate that can be further evaluated for the treatment of AML. Full article

(This article belongs to the Special Issue Molecular Pathology and Novel Therapies of Leukemia and Lymphoma)

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13 pages, 913 KiB

Open AccessArticle

Analysis of Mutational Status of IGHV, and Cytokine Polymorphisms as Prognostic Factors in Chronic Lymphocytic Leukemia: The Romanian Experience

by Beata Balla, Florin Tripon, Erzsebet Lazar and Claudia Bănescu

Int. J. Mol. Sci. 2024, 25(3), 1799; https://doi.org/10.3390/ijms25031799 - 1 Feb 2024

Viewed by 843

Abstract

The aim of the current study was to assess the associations between genetic risk factors (such as the mutational status of the IGHV gene and polymorphisms of the IL-10 and TNF-α genes) and CLL risk, prognosis, and overall survival. Another goal of this study was to evaluate the multivariate effect of the combination of multiple genetic risk factors (mutational status of the IGHV gene, somatic mutations, DNA CNVs, and cytokine SNPs) on the clinical characteristics and survival of patients. A total of 125 CLL patients and 239 healthy controls were included for comparative SNP analysis. IL-10 (rs1800896 and rs1800872) and TNF-α (rs361525 and rs1800750) SNPs and haplotypes were not associated with CLL risk. The absence of hypermutation in the IGHV gene was shown to be of important prognostic value, being associated with short OS. Further individual risk factors for short OS were an age above 65 years at diagnosis and the presence of somatic mutations and/or CNVs. In our multivariable analysis, the presence of somatic mutations and the IL-10 rs1800872 variant allele, and the association of CNVs with the IL-10 rs1800896 variant allele, were identified as risk factors for short OS. Moreover, the OS in unmutated IGHV patients was additionally affected (decreased) by the presence of CNVs and/or somatic mutations. Similarly, IL-10 rs1800896 modulated the OS in unmutated IGHV patients with CNVs. Full article

(This article belongs to the Special Issue Molecular Pathology and Novel Therapies of Leukemia and Lymphoma)

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15 pages, 6257 KiB

Open AccessArticle

Dependency of B-Cell Acute Lymphoblastic Leukemia and Multiple Myeloma Cell Lines on MEN1 Extends beyond MEN1–KMT2A Interaction

by Tatjana Magdalena Wolffhardt, Franz Ketzer, Stefano Telese, Thomas Wirth and Alexey Ushmorov

Int. J. Mol. Sci. 2023, 24(22), 16472; https://doi.org/10.3390/ijms242216472 - 17 Nov 2023

Cited by 1 | Viewed by 1145

Abstract

Menin/MEN1 is a scaffold protein that participates in proliferation, regulation of gene transcription, DNA damage repair, and signal transduction. In hematological malignancies harboring the KMT2A/MLL1 (MLLr) chromosomal rearrangements, the interaction of the oncogenic fusion protein MLLr with MEN1 has been shown to be essential. MEN1 binders inhibiting the MEN1 and KMT2A interaction have been shown to be effective against MLLr AML and B-ALL in experimental models and clinical studies. We hypothesized that in addition to the MEN1–KMT2A interaction, alternative mechanisms might be instrumental in the MEN1 dependency of leukemia. We first mined and analyzed data from publicly available gene expression databases, finding that the dependency of B-ALL cell lines on MEN1 did not correlate with the presence of MLLr. Using shRNA-mediated knockdown, we found that all tested B-ALL cell lines were sensitive to MEN1 depletion, independent of the underlying driver mutations. Most multiple myeloma cell lines that did not harbor MLLr were also sensitive to the genetic depletion of MEN1. We conclude that the oncogenic role of MEN1 is not limited to the interaction with KMT2A. Our results suggest that targeted degradation of MEN1 or the development of binders that induce global changes in the MEN1 protein structure may be more efficient than the inhibition of individual MEN1 protein interactions. Full article

(This article belongs to the Special Issue Molecular Pathology and Novel Therapies of Leukemia and Lymphoma)

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14 pages, 2511 KiB

Open AccessBrief Report

IGFBP7 Fuels the Glycolytic Metabolism in B-Cell Precursor Acute Lymphoblastic Leukemia by Sustaining Activation of the IGF1R–Akt–GLUT1 Axis

by Leonardo Luís Artico, Juliana Silveira Ruas, José Ricardo Teixeira Júnior, Natacha Azussa Migita, Gustavo Seguchi, Xinghua Shi, Silvia Regina Brandalise, Roger Frigério Castilho and José Andrés Yunes

Int. J. Mol. Sci. 2023, 24(11), 9679; https://doi.org/10.3390/ijms24119679 - 2 Jun 2023

Cited by 1 | Viewed by 1417

Abstract

Increased glycolytic metabolism plays an important role in B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL). We previously showed that IGFBP7 exerts mitogenic and prosuvival effects in ALL by promoting IGF1 receptor (IGF1R) permanence on the cell surface, thus prolonging Akt activation upon IGFs/insulin stimulation. Here, we show that sustained activation of the IGF1R–PI3K–Akt axis concurs with GLUT1 upregulation, which enhances energy metabolism and increases glycolytic metabolism in BCP-ALL. IGFBP7 neutralization with a monoclonal antibody or the pharmacological inhibition of the PI3K–Akt pathway was shown to abrogate this effect, restoring the physiological levels of GLUT1 on the cell surface. The metabolic effect described here may offer an additional mechanistic explanation for the strong negative impact seen in ALL cells in vitro and in vivo after the knockdown or antibody neutralization of IGFBP7, while reinforcing the notion that it is a valid target for future therapeutic interventions. Full article

(This article belongs to the Special Issue Molecular Pathology and Novel Therapies of Leukemia and Lymphoma)

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