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Cancers
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Novel Combination Therapies for Acute Leukemia
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Novel Combination Therapies for Acute Leukemia

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 September 2024) | Viewed by 6624

Special Issue Editors

Prof. Dr. Francesco Lanza

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Guest Editor
1. UO Ematologia, Ospedale S. Maria delle Croci, Via Randi 5, 48121 Ravenna, Italy
2. Department of Medicine and Surgery (DIMEC), University of Bologna, 40126 Bologna, Italy
Interests: acute myeloid leukemia; acute lymphoblastic leukemia; stem cell transplantation (autologous and allogeneic); novel therapies; stem cell manipulation; cryopreservation and characterization; cell therapy in onco-hematological disorders
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Attilio Olivieri

E-Mail Website
Guest Editor
Stem Cell Transplant Unit, Hematology Department, DISCLIMO-Università Politecnica delle Marche, 60126 Ancona, Italy
Interests: allogenic stem cell transplantation; graft versus host disease; stem cell mobilization; novel drugs

Special Issue Information

Dear Colleagues,

Acute leukemia is a heterogeneous group of diseases characterized by clonal expansion of immature blast cells in the peripheral blood, bone marrow and other tissues resulting in bone marrow failure. Over the last ten years, a great number of molecular aberrations have been identified in either acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), making these disease optimal candidates for the development of investigational drugs targeting driver genetic mutations. It is now evident that most of these abnormalities could trigger the development of acute leukemia or have an important role in the pathogenesis and/or clonal expansion of leukemia. The routine application of novel molecular biology technologies such as next generation sequencing (NGS) and whole genome sequencing (WHS) has facilitated the development of such genetic lesions, with relevant clinical and therapeutical application. Recent publications have shown that these somatically acquired genetic lesions are particularly important for diagnostic classification and risk assessment in patients with AML and ALL. Systematic studies of the genomic landscape of AML, such as analyses of data from the Cancer Genome Atlas, have generated a catalogue of leukemia-associated genes that is increasingly comprehensive and exhaustive, marking AML as a complex, dynamic disease. Furthermore, an increasing number of clinical trials have been testing “druggable” mutations in the context of novel targeted therapies, making this area more and more interesting in several areas of investigations.

This Special Issue of Cancers (“Novel Combination Therapies for Acute Leukemias” ) focuses on novel therapeutical approaches in acute leukemias and related diseases, and aims to collect original papers and commentaries in several areas of investigations concerning AML and ALL, including preclinical, clinical, and biological studies.

Prof. Dr. Francesco Lanza
Prof. Dr. Attilio Olivieri
Guest Editors

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 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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

  • acute myeloid leukemia
  • acute lymphoblastic leukemia
  • molecular aberrations
  • novel therapies
  • druggable genetic lesions

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Published Papers (3 papers)

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Research

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10 pages, 806 KiB  
Article
Low WT1 Expression Identifies a Subset of Acute Myeloid Leukemia with a Distinct Genotype
by Michela Rondoni, Giovanni Marconi, Annalisa Nicoletti, Barbara Giannini, Elisa Zuffa, Maria Benedetta Giannini, Annamaria Mianulli, Marianna Norata, Federica Monaco, Irene Zaccheo, Serena Rocchi, Beatrice Anna Zannetti, Adele Santoni, Claudio Graziano, Monica Bocchia and Francesco Lanza
Cancers 2025, 17(7), 1213; https://doi.org/10.3390/cancers17071213 - 3 Apr 2025
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Abstract
Background: Wilms’ tumor gene 1 (WT1) is a critical player in acute myeloid leukemia (AML), often serving as a biomarker for measurable residual disease (MRD). The WT1 gene is overexpressed in the majority of AML cases at diagnosis, with apparently no [...] Read more.
Background: Wilms’ tumor gene 1 (WT1) is a critical player in acute myeloid leukemia (AML), often serving as a biomarker for measurable residual disease (MRD). The WT1 gene is overexpressed in the majority of AML cases at diagnosis, with apparently no correlation with prognosis, and in the meantime, its role in patients with low-level expression is still undefined. This study investigates the mutational landscape and clinical outcomes of AML patients with low WT1 expression at diagnosis. Methods: We analyzed 34 AML patients with low WT1 expression (WT1/ABL1 < 250) diagnosed and treated from 2013 to 2017 at three institutions. Next-generation sequencing (NGS) was employed to investigate the mutational status of 32 genes commonly mutated in AML. The presence of specific mutations, as well as clinical outcomes, was compared to the general AML population. Results: Patients with low WT1 expression showed a significantly higher mutational burden, with a median of 3.4 mutations per patient, compared to the general AML population. Notably, clonal hematopoiesis (CHIP) or myelodysplasia-related (MR) mutations, particularly in ASXL1, TET2, and SRSF2, were present in most patients with low WT1 expression. All but one case of NPM1- or FLT3-mutant AML in the low-WT1 cohort harbored more CHIP or MR mutations. Patients with low WT1 expression had an overall survival (OS) that was superimposable to the OS expected in MR AML. Conclusions: Low WT1 expression in AML is associated with a distinct and complex mutational profile, marked by frequent CHIP and MR mutations. Full article
(This article belongs to the Special Issue Novel Combination Therapies for Acute Leukemia)
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16 pages, 3100 KiB  
Article
Synergistic Effects of the RARalpha Agonist Tamibarotene and the Menin Inhibitor Revumenib in Acute Myeloid Leukemia Cells with KMT2A Rearrangement or NPM1 Mutation
by Maximilian Fleischmann, Julia Bechwar, Diana Voigtländer, Mike Fischer, Ulf Schnetzke, Andreas Hochhaus and Sebastian Scholl
Cancers 2024, 16(7), 1311; https://doi.org/10.3390/cancers16071311 - 28 Mar 2024
Cited by 5 | Viewed by 2434
Abstract
Inhibition of menin in acute myeloid leukemia (AML) harboring histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or the mutated Nucleophosmin gene (NPM1c) is considered a novel and effective treatment approach in these patients. However, rapid acquisition of resistance mutations can impair treatment success. In [...] Read more.
Inhibition of menin in acute myeloid leukemia (AML) harboring histone-lysine-N-methyltransferase 2A rearrangement (KMT2Ar) or the mutated Nucleophosmin gene (NPM1c) is considered a novel and effective treatment approach in these patients. However, rapid acquisition of resistance mutations can impair treatment success. In patients with elevated retinoic acid receptor alpha (RARA) expression levels, promising effects are demonstrated by the next-generation RARalpha agonist tamibarotene, which restores differentiation or induces apoptosis. In this study, the combination of revumenib and tamibarotene was investigated in various KMT2Ar or NPM1c AML cell lines and patient-derived blasts, focusing on the potential synergistic induction of differentiation or apoptosis. Both effects were analyzed by flow cytometry and validated by Western blot analysis. Synergy calculations were performed using viability assays. Regulation of the relevant key mediators for the MLL complex were quantified by RT-qPCR. In MV4:11 cells characterized by the highest relative mRNA levels of RARA, highly synergistic induction of apoptosis is demonstrated upon combination treatment. Induction of apoptosis by combined treatment of MV4:11 cells is accompanied by pronounced induction of the pro-apoptotic protein BAX and a synergistic reduction in CDK6 mRNA levels. In MOLM13 and OCI-AML3 cells, an increase in differentiation markers like PU.1 or a decreased ratio of phosphorylated to total CEBPA is demonstrated. In parts, corresponding effects were observed in patient-derived AML cells carrying either KMT2Ar or NPM1c. The impact of revumenib on KMT2Ar or NPM1c AML cells was significantly enhanced when combined with tamibarotene, demonstrating synergistic differentiation or apoptosis initiation. These findings propose promising strategies for relapsed/refractory AML patients with defined molecular characteristics. Full article
(This article belongs to the Special Issue Novel Combination Therapies for Acute Leukemia)
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Review

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20 pages, 3034 KiB  
Review
Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation
by Can Chen and Ji Zhang
Cancers 2024, 16(6), 1171; https://doi.org/10.3390/cancers16061171 - 16 Mar 2024
Cited by 5 | Viewed by 3046
Abstract
Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino [...] Read more.
Cancer cells demand amino acids beyond their usage as “building blocks” for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia. Full article
(This article belongs to the Special Issue Novel Combination Therapies for Acute Leukemia)
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