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Biomedicines
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Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia
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Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 April 2024) | Viewed by 4810

Special Issue Editor

Dr. Alessandra Sperotto

E-Mail Website
Guest Editor
Onco Hematology, Department of Oncology, Veneto Institute of Oncology, IOV-IRCCS, 31033 Padua, Italy
Interests: acute myeloid leukemia; hematopoietic stem cell transplantation; target therapies; bone marrow microenvironment

Special Issue Information

Dear Colleagues,

Acute myeloid leukemia (AML) is an extremely heterogeneous disease and remains difficult to cure. A better understanding of the AML biological landscape allows for the development of new target therapy and biological strategies that may open a new perspective, even in unfavorable populations such as relapse/refractory or older patients. This new therapeutic armamentarium includes Bcl-2 inhibitors, FLT3 inhibitors, IDH1-2 inhibitors, and many other small synthetic molecules. Not only the recognition of specific gene mutations, but also the identification of peculiar signature pathways, such as Homeobox gene A and B overexpression, can help the identification of shared therapeutic targets, as is currently the case for menin inhibitors. Interaction between AML blasts and the microenvironment and the remaining immune compartment are still poorly understood and can partially justify the largely heterogeneous course of the disease, even in the era of new target therapies. The rational use of these compounds in clinical practice cannot, therefore, disregard a better understanding of resistance and immune-escape mechanisms.

This Special Issue will be dedicated to recent progress in understanding the pathogenetic AML landscape and possible therapeutic strategies. We invite authors to submit original research and review articles. Suitable topics may include, but are not limited to:

  • Potential targeted therapies and combination strategy in acute myeloid leukemia;
  • The pathogenesis of acute myeloid leukemia;
  • Bone marrow microenvironment in acute myeloid leukemia;
  • Precision medicine in acute myeloid leukemia;
  • Mechanism of resistance.

Dr. Alessandra Sperotto
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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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
  • target therapies
  • molecular pathogenesis
  • biological therapy
  • precision medicine

Published Papers (4 papers)

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Review

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23 pages, 842 KiB  
Review
Measurable Residual Disease Detection in Acute Myeloid Leukemia: Current Challenges and Future Directions
by Jennifer Moritz, Antonia Schwab, Andreas Reinisch, Armin Zebisch, Heinz Sill and Albert Wölfler
Biomedicines 2024, 12(3), 599; https://doi.org/10.3390/biomedicines12030599 - 07 Mar 2024
Viewed by 848
Abstract
Acute myeloid leukemia (AML) is an aggressive malignant disease with a high relapse rate due to the persistence of chemoresistant cells. To some extent, these residual cells can be traced by sensitive flow cytometry and molecular methods resulting in the establishment of measurable [...] Read more.
Acute myeloid leukemia (AML) is an aggressive malignant disease with a high relapse rate due to the persistence of chemoresistant cells. To some extent, these residual cells can be traced by sensitive flow cytometry and molecular methods resulting in the establishment of measurable residual disease (MRD). The detection of MRD after therapy represents a significant prognostic factor for predicting patients’ individual risk of relapse. However, due to the heterogeneity of the disease, a single sensitive method for MRD detection applicable to all AML patients is lacking. This review will highlight the advantages and limitations of the currently available detection methods—PCR, multiparameter flow cytometry, and next generation sequencing—and will discuss emerging clinical implications of MRD test results in tailoring treatment of AML patients. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)
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15 pages, 556 KiB  
Review
MicroRNAs Associated with a Bad Prognosis in Acute Myeloid Leukemia and Their Impact on Macrophage Polarization
by Laura Jimbu, Oana Mesaros, Corina Joldes, Alexandra Neaga, Laura Zaharie and Mihnea Zdrenghea
Biomedicines 2024, 12(1), 121; https://doi.org/10.3390/biomedicines12010121 - 07 Jan 2024
Viewed by 1245
Abstract
MicroRNAs (miRNAs) are short, non-coding ribonucleic acids (RNAs) associated with gene expression regulation. Since the discovery of the first miRNA in 1993, thousands of miRNAs have been studied and they have been associated not only with physiological processes, but also with various diseases [...] Read more.
MicroRNAs (miRNAs) are short, non-coding ribonucleic acids (RNAs) associated with gene expression regulation. Since the discovery of the first miRNA in 1993, thousands of miRNAs have been studied and they have been associated not only with physiological processes, but also with various diseases such as cancer and inflammatory conditions. MiRNAs have proven to be not only significant biomarkers but also an interesting therapeutic target in various diseases, including cancer. In acute myeloid leukemia (AML), miRNAs have been regarded as a welcome addition to the limited therapeutic armamentarium, and there is a vast amount of data on miRNAs and their dysregulation. Macrophages are innate immune cells, present in various tissues involved in both tissue repair and phagocytosis. Based on their polarization, macrophages can be classified into two groups: M1 macrophages with pro-inflammatory functions and M2 macrophages with an anti-inflammatory action. In cancer, M2 macrophages are associated with tumor evasion, metastasis, and a poor outcome. Several miRNAs have been associated with a poor prognosis in AML and with either the M1 or M2 macrophage phenotype. In the present paper, we review miRNAs with a reported negative prognostic significance in cancer with a focus on AML and analyze their potential impact on macrophage polarization. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)
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Other

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22 pages, 1554 KiB  
Systematic Review
Gemtuzumab Ozogamicin in Acute Myeloid Leukemia: Efficacy, Toxicity, and Resistance Mechanisms—A Systematic Review
by Aurelia Collados-Ros, Manuel Muro and Isabel Legaz
Biomedicines 2024, 12(1), 208; https://doi.org/10.3390/biomedicines12010208 - 17 Jan 2024
Viewed by 1334
Abstract
Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on [...] Read more.
Acute myeloid leukemia (AML) is a diverse group of leukemias characterized by the uncontrolled proliferation of clonal neoplastic hematopoietic precursor cells with chromosomal rearrangements and multiple gene mutations and the impairment of normal hematopoiesis. Current efforts to improve AML outcomes have focused on developing targeted therapies that may allow for improved antileukemic effects while reducing toxicity significantly. Gemtuzumab ozogamicin (GO) is one of the most thoroughly studied molecularly targeted therapies in adults. GO is a monoclonal antibody against CD33 IgG4 linked to the cytotoxic drug calicheamicin DMH. The use of GO as a chemotherapeutic agent is not generalized for all patients who suffer from AML, particularly for those whose health prevents them from using intensive conventional chemotherapy, in which case it can be used on its own, and those who have suffered a first relapse, where its combination with other chemotherapeutic agents is possible. This systematic review aimed to comprehensively evaluate GO, focusing on its molecular structure, mode of action, pharmacokinetics, recommended dosage, resistance mechanisms, and associated toxicities to provide valuable information on the potential benefits and risks associated with its clinical use. A systematic review of eight scientific articles from 2018 to 2023 was conducted using PRISMA analysis. The results showed that GO treatment activates proapoptotic pathways and induces double-strand breaks, initiating DNA repair mechanisms. Cells defective in DNA repair pathways are susceptible to GO cytotoxicity. GO has recommended doses for newly diagnosed CD33+ AML in combination or as a single agent. Depending on the treatment regimen and patient status, GO doses vary for induction, consolidation, and continuation cycles. Multidrug resistance (MDR) involving P-glycoprotein (P-gp) is associated with GO resistance. The overexpression of P-gp reduces GO cytotoxicity; inhibitors of P-gp can restore sensitivity. Mitochondrial pathway activation and survival signaling pathways are linked to GO resistance. Other resistance mechanisms include altered pharmacokinetics, reduced binding ability, and anti-apoptotic mechanisms. GO has limited extramedullary toxicity compared to other AML treatments and may cause hepatic veno-occlusive disease (HVOD). The incidence of hepatic HVOD after GO therapy is higher in patients with high tumor burden. Hematological side effects and hepatotoxicity are prominent, with thrombocytopenia and neutropenia observed. In conclusion, GO’s reintroduction in 2017 followed a thorough FDA review considering its altered dose, dosing schedule, and target population. The drug’s mechanism involves CD33 targeting and calicheamicin-induced DNA damage, leading to apoptosis and resistance mechanisms, including MDR and survival signaling, which impact treatment outcomes. Despite limited extramedullary toxicity, GO is associated with hematological side effects and hepatotoxicity. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)
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10 pages, 1307 KiB  
Case Report
Case Report of a DDX41 Germline Mutation in a Family with Multiple Relatives Suffering from Leukemia
by Jan Nicolai Wagner, Maximilian Al-Bazaz, Anika Forstreuter, Mohammad Ibrahim Hammada, Jurek Hille, Dzhoy Papingi, Carsten Bokemeyer and Walter Fiedler
Biomedicines 2024, 12(1), 64; https://doi.org/10.3390/biomedicines12010064 - 27 Dec 2023
Viewed by 1050
Abstract
Introduction: Previously, it was assumed that genetic influence played a minor role in acute myeloid leukemia (AML). Increasing evidence of germline mutations has emerged, such as DDX41 germline mutation associated with familial AML. Case presentation: A 64-year-old male patient presented with reduced exercise [...] Read more.
Introduction: Previously, it was assumed that genetic influence played a minor role in acute myeloid leukemia (AML). Increasing evidence of germline mutations has emerged, such as DDX41 germline mutation associated with familial AML. Case presentation: A 64-year-old male patient presented with reduced exercise tolerance and shortness of breath. Following confirmation of AML diagnosis, the patient was enrolled into the AMLSG-30-18 study with a requirement for allogenic stem cell transplantation. The sister was initially selected as a fully HLA-matched donor. However, the family history showed risks for familial AML. Due to the striking family history, further diagnostic steps were initiated to detect a germline mutation. Methods: Using NGS in the patients’ bone marrow AML sample, a DDX41 mutation with a VAF of 49% was detected, raising the possibility of a germline mutation. DNA from cheek swabs and eyebrows were tested for the presence of the DDX41 mutation in all siblings. Results: DDX41 germline mutation was detected in 5 out of 6 siblings. The sister was excluded as a related donor and the search for an unrelated donor was initiated. Conclusion: Obtaining family history of cancer patients plays a crucial role in oncology. If a germline mutation is suspected, further family work-up should be initiated. Full article
(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)
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