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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 (20 October 2024) | Viewed by 16826

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Dr. Luca Lo Nigro

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Center of Pediatric Hematology-Oncology, Azienda Policlinico–San Marco, 95123 Catania, Italy
Interests: acute lymphoblastic leukemia; acute myeloid leukemia; biomarkers; new targets of disease; novel immunotherapy; leukemia stem cell
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Dear Colleagues,

Acute leukemia is a big killer. The scientific community has made significant efforts to understand the molecular bases of this disease, in order to identify specific biomarkers and/or target aberrations to be used for designing a tailored treatment. Although the current use of chemotherapy leads to a high rate of survival, in children, acute leukemias represent the greatest cause of death in the pediatric population with cancer. In adult settings, despite a high rate of remission at the end of induction therapy, relapse is a major concern in the management of patients with acute leukemia. Thus, it is essential to undertake efforts in translational research, starting from basic science and translating into clinical interventions. Therefore, the main scope of this Special Issue is to reveal the molecular mechanisms of basic research studies on acute leukemia with a clear and future translational impact on treatment, including novel potential biomarkers and/or target for tailored treatment.

The International Journal of Molecular Sciences invites both reviews and original articles, please note that pure clinical research or model studies, survey studies, and correlation research are out of the scope of IJMS. However, clinical or model submissions with biomolecular experiments are welcomed.

Dr. Luca Lo Nigro
Guest Editor

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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

acute lymphoblastic leukemia (ALL)
acute myeloid leukemia (AML)
genomic findings
post-genomic findings
targeted therapies
immunotherapies
novel markers

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Related Special Issue

Acute Leukemia: From Basic Research to Clinical Application, Second Edition in International Journal of Molecular Sciences

Published Papers (10 papers)

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Research

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13 pages, 1707 KiB

Open AccessArticle

Characterization of CK2, MYC and ERG Expression in Biological Subgroups of Children with Acute Lymphoblastic Leukemia

by Luca Lo Nigro, Marta Arrabito, Nellina Andriano, Valeria Iachelli, Manuela La Rosa and Paola Bonaccorso

Int. J. Mol. Sci. 2025, 26(3), 1076; https://doi.org/10.3390/ijms26031076 - 26 Jan 2025

Viewed by 868

Abstract

Despite the excellent survival rate, relapse occurs in 20% of children with ALL. Deep analyses of cell signaling pathways allow us to identify new markers and/or targets promising more effective and less toxic therapy. We analyzed 61 diagnostic samples collected from 35 patients with B- and 26 with T-ALL, respectively. The expression of CK2, MYC and ERG genes using Sybr-Green assay and the comparative 2-ΔΔCt method using 20 healthy donors (HDs) was evaluated. We observed a statistically significant difference in CK2 expression in non-HR (p = 0.010) and in HR (p = 0.0003) T-ALL cases compared to HDs. T-ALL patients with PTEN-Exon7 mutation, IKZF1 and CDKN2A deletions showed high CK2 expression. MYC expression was higher in pediatric T-ALL patients than HDs (p = 0.019). Surprisingly, we found MYC expression to be higher in non-HR than in HR T-ALL patients. TLX3 (HOX11L2)-rearranged T-ALLs (27%) in association with CRLF2 overexpression (23%) showed very high MYC expression. In B-ALLs, we detected CK2 expression higher than HDs and MYC overexpression in HR compared to non-HR patients, particularly in MLL-rearranged B-ALLs. We observed a strong difference in ERG expression between pediatric T- and B-ALL cases. In conclusion, we confirmed CK2 as a prognostic marker and a therapeutic target. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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15 pages, 2879 KiB

Open AccessArticle

Hyaluronan-Mediated Motility Receptor (HMMR) Overexpression Is Correlated with Poor Survival in Patients with B-ALL

by Josselen Carina Ramírez-Chiquito, Vanessa Villegas-Ruíz, Isabel Medina-Vera, Itzel Sánchez-Cruz, Christian Lizette Frías-Soria, Marcela Concepción Caballero Palacios, Gabriela Antonio-Andrés, Alejandra Elizabeth Rubio-Portillo, Liliana Velasco-Hidalgo, Mario Perezpeña-Diazconti, Cesar Alejandro Galván-Diaz, Norma Candelaria López-Santiago, Sara Huerta-Yepez and Sergio Juárez-Méndez

Int. J. Mol. Sci. 2025, 26(2), 744; https://doi.org/10.3390/ijms26020744 - 16 Jan 2025

Viewed by 922

Abstract

Acute lymphoblastic leukemia (ALL) is a malignant neoplasm with the highest incidence in the pediatric population. Although the 5-year overall survival is greater than 85%, in emerging countries such as Mexico, the mortality rate is high. In Mexico, B-ALL is the most common type of childhood cancer; different characteristics suggest the presence of the disease; however, the prognosis is dependent on clinical and laboratory features, and no adverse prognostic molecular marker for B-ALL has yet been identified. The present research aimed to identify the prognostic value of HMMR expression in pediatric patients with B-ALL. The differential expression profile of B-ALL cells was determined via in silico analysis, and HMMR expression was subsequently measured via qRT–PCR and immunocytochemistry. The results were statistically analyzed via the ROUT test, Kolmogorov–Smirnov Z test, and Mann–Whitney U test. ROC curves and the Youden index were constructed, and Kaplan–Meier curves were plotted. We found that HMMR expression was increased in B-ALL patients (p < 0.0001). We observed that high expression was related to poor prognosis (p < 0.05). We observed that high expression was related to poor prognosis (p < 0.05). The increase in HMMR expression could be a potential early molecular prognostic marker and/or a new target in childhood B-ALL patients. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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21 pages, 3279 KiB

Open AccessArticle

Evaluation of 3D-Printed Microfluidic Structures for Use in AML-Specific Biomarker Detection of PML::RARA

by Benedikt Emde, Karsten Niehaus and Lara Tickenbrock

Int. J. Mol. Sci. 2025, 26(2), 497; https://doi.org/10.3390/ijms26020497 - 9 Jan 2025

Viewed by 935

Abstract

An obstacle for many microfluidic developments is the fabrication of its structures, which is often complex, time-consuming, and expensive. Additive manufacturing can help to reduce these barriers. This study investigated whether the results of a microfluidic assay for the detection of the promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) fusion protein (PML::RARA), and thus for the differential diagnosis of acute promyelocytic leukemia (APL), could be transferred from borosilicate glass microfluidic structures to additively manufactured fluidics. Digital light processing (DLP) and stereolithography (SLA) printers as well as different photopolymerizable methacrylate-based resins were tested for fabrication of the fluidics. To assess suitability, both print resolution and various physical properties, serializability, biocompatibility, and functionalization with biological molecules were analyzed. The results show that additively manufactured microfluidics are suitable for application in leukemia diagnostics. This was demonstrated by transferring the microfluidic sandwich enzyme-linked immunosorbent assay (ELISA) for PML::RARA onto the surface of magnetic microparticles from a glass structure to three-dimensional (3D)-printed parts. A comparison with conventional glass microstructures suggests lower sensitivity but highlights the potential of additive manufacturing for prototyping microfluidics. This may contribute to the wider use of microfluidics in biotechnological or medical applications. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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23 pages, 6692 KiB

Open AccessArticle

Discovery of NFκB2-Coordinated Dual Regulation of Mitochondrial and Nuclear Genomes Leads to an Effective Therapy for Acute Myeloid Leukemia

by Yi Xu, David J. Baylink, Jeffrey Xiao, Lily Tran, Vinh Nguyen, Brandon Park, Ismael Valladares, Scott Lee, Kevin Codorniz, Laren Tan, Chien-Shing Chen, Hisham Abdel-Azim, Mark E. Reeves, Hamid Mirshahidi, Guido Marcucci and Huynh Cao

Int. J. Mol. Sci. 2024, 25(15), 8532; https://doi.org/10.3390/ijms25158532 - 5 Aug 2024

Viewed by 1589

Abstract

Acute myeloid leukemia (AML) has a poor survival rate for both pediatric and adult patients due to its frequent relapse. To elucidate the bioenergetic principle underlying AML relapse, we investigated the transcriptional regulation of mitochondrial–nuclear dual genomes responsible for metabolic plasticity in treatment-resistant blasts. Both the gain and loss of function results demonstrated that NFκB2, a noncanonical transcription factor (TF) of the NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) family, can control the expression of TFAM (mitochondrial transcription factor A), which is known to be essential for metabolic biogenesis. Furthermore, genetic tracking and promoter assays revealed that NFκB2 is in the mitochondria and can bind the specific “TTGGGGGGTG” region of the regulatory D-loop domain to activate the light-strand promoter (LSP) and heavy-strand promoter 1 (HSP1), promoters of the mitochondrial genome. Based on our discovery of NFκB2′s novel function of regulating mitochondrial–nuclear dual genomes, we explored a novel triplet therapy including inhibitors of NFκB2, tyrosine kinase, and mitochondrial ATP synthase that effectively eliminated primary AML blasts with mutations of the FMS-related receptor tyrosine kinase 3 (FLT3) and displayed minimum toxicity to control cells ex vivo. As such, effective treatments for AML must include strong inhibitory actions on the dual genomes mediating metabolic plasticity to improve leukemia prognosis. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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21 pages, 2344 KiB

Open AccessArticle

Synergistic Enhancement of Chemotherapy-Induced Cell Death and Antitumor Efficacy against Tumoral T-Cell Lymphoblasts by IMMUNEPOTENT CRP

by Ana Luisa Rivera-Lazarín, Kenny Misael Calvillo-Rodríguez, Mizael Izaguirre-Rodríguez, José Manuel Vázquez-Guillén, Ana Carolina Martínez-Torres and Cristina Rodríguez-Padilla

Int. J. Mol. Sci. 2024, 25(14), 7938; https://doi.org/10.3390/ijms25147938 - 20 Jul 2024

Cited by 2 | Viewed by 1631

Abstract

T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL), present significant challenges to treatment due to their aggressive nature and chemoresistance. Chemotherapies remain a mainstay for their management, but the aggressiveness of these cancers and their associated toxicities pose limitations. Immunepotent CRP (ICRP), a bovine dialyzable leukocyte extract, has shown promise in inducing cytotoxicity against various cancer types, including hematological cancers. In this study, we investigated the combined effect of ICRP with a panel of chemotherapies on cell line models of T-ALL and T-LBL (CEM and L5178Y-R cells, respectively) and its impact on immune system cells (peripheral blood mononuclear cells, splenic and bone marrow cells). Our findings demonstrate that combining ICRP with chemotherapies enhances cytotoxicity against tumoral T-cell lymphoblasts. ICRP + Cyclophosphamide (CTX) cytotoxicity is induced through a caspase-, reactive oxygen species (ROS)-, and calcium-dependent mechanism involving the loss of mitochondrial membrane potential, an increase in ROS production, and caspase activation. Low doses of ICRP in combination with CTX spare non-tumoral immune cells, overcome the bone marrow-induced resistance to CTX cell death, and improves the CTX antitumor effect in vivo in syngeneic Balb/c mice challenged with L5178Y-R. This led to a reduction in tumor volume and a decrease in Ki-67 proliferation marker expression and the granulocyte/lymphocyte ratio. These results set the basis for further research into the clinical application of ICRP in combination with chemotherapeutic regimens for improving outcomes in T-cell malignancies. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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21 pages, 3657 KiB

Open AccessArticle

Nonclinical Evaluation of Single-Mutant E. coli Asparaginases Obtained by Double-Mutant Deconvolution: Improving Toxicological, Immune and Inflammatory Responses

by Grace Ruiz-Lara, Tales A. Costa-Silva, Jorge Javier Muso-Cachumba, Johanna Cevallos Espinel, Marina Gabriel Fontes, Mitla Garcia-Maya, Khondaker Miraz Rahman, Carlota de Oliveira Rangel-Yagui and Gisele Monteiro

Int. J. Mol. Sci. 2024, 25(11), 6008; https://doi.org/10.3390/ijms25116008 - 30 May 2024

Viewed by 1272

Abstract

Acute lymphoblastic leukaemia is currently treated with bacterial L-asparaginase; however, its side effects raise the need for the development of improved and efficient novel enzymes. Previously, we obtained low anti-asparaginase antibody production and high serum enzyme half-life in mice treated with the P40S/S206C mutant; however, its specific activity was significantly reduced. Thus, our aim was to test single mutants, S206C and P40S, through in vitro and in vivo assays. Our results showed that the drop in specific activity was caused by P40S substitution. In addition, our single mutants were highly stable in biological environment simulation, unlike the double-mutant P40S/S206C. The in vitro cell viability assay demonstrated that mutant enzymes have a higher cytotoxic effect than WT on T-cell-derived ALL and on some solid cancer cell lines. The in vivo assays were performed in mice to identify toxicological effects, to evoke immunological responses and to study the enzymes’ pharmacokinetics. From these tests, none of the enzymes was toxic; however, S206C elicited lower physiological changes and immune/allergenic responses. In relation to the pharmacokinetic profile, S206C exhibited twofold higher activity than WT and P40S two hours after injection. In conclusion, we present bioengineered E. coli asparaginases with high specific enzyme activity and fewer side effects. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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Review

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40 pages, 5235 KiB

Open AccessReview

Unlocking the Heterogeneity in Acute Leukaemia: Dissection of Clonal Architecture and Metabolic Properties for Clinical Interventions

by Martina Maria Capelletti, Orsola Montini, Emilio Ruini, Sarah Tettamanti, Angela Maria Savino and Jolanda Sarno

Int. J. Mol. Sci. 2025, 26(1), 45; https://doi.org/10.3390/ijms26010045 - 24 Dec 2024

Viewed by 1656

Abstract

Genetic studies of haematological cancers have pointed out the heterogeneity of leukaemia in its different subpopulations, with distinct mutations and characteristics, impacting the treatment response. Next-generation sequencing (NGS) and genome-wide analyses, as well as single-cell technologies, have offered unprecedented insights into the clonal heterogeneity within the same tumour. A key component of this heterogeneity that remains unexplored is the intracellular metabolome, a dynamic network that determines cell functions, signalling, epigenome regulation, immunity and inflammation. Understanding the metabolic diversities among cancer cells and their surrounding environments is therefore essential in unravelling the complexities of leukaemia and improving therapeutic strategies. Here, we describe the currently available methodologies and approaches to addressing the dynamic heterogeneity of leukaemia progression. In the second section, we focus on metabolic leukaemic vulnerabilities in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Lastly, we provide a comprehensive overview of the most interesting clinical trials designed to target these metabolic dependencies, highlighting their potential to advance therapeutic strategies in leukaemia treatment. The integration of multi-omics data for cancer identification with the metabolic states of tumour cells will enable a comprehensive “micro-to-macro” approach for the refinement of clinical practices and delivery of personalised therapies. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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25 pages, 660 KiB

Open AccessReview

Precision Medicine Approaches in Acute Myeloid Leukemia with Adverse Genetics

by Nicole Santoro, Prassede Salutari, Mauro Di Ianni and Andrea Marra

Int. J. Mol. Sci. 2024, 25(8), 4259; https://doi.org/10.3390/ijms25084259 - 11 Apr 2024

Cited by 3 | Viewed by 3417

Abstract

The treatment of acute myeloid leukemia (AML) with adverse genetics remains unsatisfactory, with very low response rates to standard chemotherapy and shorter durations of remission commonly observed in these patients. The complex biology of AML with adverse genetics is continuously evolving. Herein, we discuss recent advances in the field focusing on the contribution of molecular drivers of leukemia biogenesis and evolution and on the alterations of the immune system that can be exploited with immune-based therapeutic strategies. We focus on the biological rationales for combining targeted therapy and immunotherapy, which are currently being investigated in ongoing trials, and could hopefully ameliorate the poor outcomes of patients affected by AML with adverse genetics. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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9 pages, 895 KiB

Open AccessBrief Report

Rare Drivers at Low Prevalence with High Cancer Effects in T-Cell and B-Cell Pediatric Acute Lymphoblastic Leukemia

by Jeffrey D. Mandell, Saathvika Diviti, Mina Xu and Jeffrey P. Townsend

Int. J. Mol. Sci. 2024, 25(12), 6589; https://doi.org/10.3390/ijms25126589 - 15 Jun 2024

Viewed by 2027

Abstract

The genomic analyses of pediatric acute lymphoblastic leukemia (ALL) subtypes, particularly T-cell and B-cell lineages, have been pivotal in identifying potential therapeutic targets. Typical genomic analyses have directed attention toward the most commonly mutated genes. However, assessing the contribution of mutations to cancer phenotypes is crucial. Therefore, we estimated the cancer effects (scaled selection coefficients) for somatic substitutions in T-cell and B-cell cohorts, revealing key insights into mutation contributions. Cancer effects for well-known, frequently mutated genes like NRAS and KRAS in B-ALL were high, which underscores their importance as therapeutic targets. However, less frequently mutated genes IL7R, XBP1, and TOX also demonstrated high cancer effects, suggesting pivotal roles in the development of leukemia when present. In T-ALL, KRAS and NRAS are less frequently mutated than in B-ALL. However, their cancer effects when present are high in both subtypes. Mutations in PIK3R1 and RPL10 were not at high prevalence, yet exhibited some of the highest cancer effects in individual T-cell ALL patients. Even CDKN2A, with a low prevalence and relatively modest cancer effect, is potentially highly relevant for the epistatic effects that its mutated form exerts on other mutations. Prioritizing investigation into these moderately frequent but potentially high-impact targets not only presents novel personalized therapeutic opportunities but also enhances the understanding of disease mechanisms and advances precision therapeutics for pediatric ALL. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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9 pages, 794 KiB

Open AccessCase Report

A Rare Case of Methemoglobinemia after Ifosfamide Infusion in a 3-Year-Old Patient Treated for T-ALL

by Maria Suprunowicz, Katarzyna Marcinkiewicz, Elżbieta Leszczyńska, Anna Krętowska-Grunwald, Marcin Płonowski, Mariola Tałałaj, Łucja Dakowicz, Maryna Krawczuk-Rybak and Małgorzata Sawicka-Żukowska

Int. J. Mol. Sci. 2024, 25(7), 3789; https://doi.org/10.3390/ijms25073789 - 28 Mar 2024

Cited by 1 | Viewed by 1426

Abstract

Methemoglobinemia is a potentially life-threatening, rare condition in which the oxygen-carrying capacity of hemoglobin is diminished. We present the case of a 3-year-old boy treated for T-cell acute lymphoblastic leukemia (T-ALL) who developed methemoglobinemia (MetHb 57.1%) as a side effect of ifosfamide administration. Due to his critical condition, the patient was transferred to the intensive care unit (ICU). The therapy included methylene blue administration, an exchange transfusion, catecholamine infusion, and steroids. Improving the general condition allowed for continuing chemotherapy without ifosfamide and completion of the HR2 block. Vigilance for methemoglobinemia as a very rare side effect should be widespread when using ifosfamide in the treatment protocols. Full article

(This article belongs to the Special Issue Acute Leukemia: From Basic Research to Clinical Application)

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