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23 pages, 6768 KiB

Open AccessArticle

The Proteasome-Family-Members-Based Prognostic Model Improves the Risk Classification for Adult Acute Myeloid Leukemia

by Guangying Sheng, Jingfen Tao, Peng Jin, Yilu Li, Wen Jin and Kankan Wang

Biomedicines 2024, 12(9), 2147; https://doi.org/10.3390/biomedicines12092147 - 22 Sep 2024

Viewed by 1572

Abstract

Background: The accumulation of diverse molecular and cytogenetic variations contributes to the heterogeneity of acute myeloid leukemia (AML), a cluster of hematologic malignancies that necessitates enhanced risk evaluation for prognostic prediction and therapeutic guidance. The ubiquitin–proteasome system plays a crucial role in AML; [...] Read more.

Background: The accumulation of diverse molecular and cytogenetic variations contributes to the heterogeneity of acute myeloid leukemia (AML), a cluster of hematologic malignancies that necessitates enhanced risk evaluation for prognostic prediction and therapeutic guidance. The ubiquitin–proteasome system plays a crucial role in AML; however, the specific contributions of 49 core proteasome family members (PSMs) in this context remain largely unexplored. Methods: The expression and survival significance of 49 PSMs in AML were evaluated using the data from BeatAML2.0, TCGA, and the GEO database, mainly through the K-M plots, differential genes enrichment analysis, and candidate compounds screening via R language and statistical software. Results: we employed LASSO and Cox regression analyses and developed a model comprising three PSMs (PSMB8, PSMG1, and PSMG4) aimed at predicting OS in adult AML patients, utilizing expression profiles from the BeatAML2.0 training datasets. Patients with higher risk scores were predominantly found in the AML–M2 subtype, exhibited poorer ELN stratification, showed no complete remission following induction therapies, and had a higher mortality status. Consistently, significantly worse OS was observed in high-risk patients across both the training and three validation datasets, underscoring the robust predictive capability of the three-PSMs model for AML outcomes. This model elucidated the distinct genetic abnormalities landscape between high- and low-risk groups and enhanced the ELN risk stratification system. Ultimately, the three-PSMs risk score captured AML-specific gene expression signatures, providing a molecular basis for selecting potential therapeutic agents. Conclusions: In summary, these findings manifested the significant potential of the PSM model for predicting AML survival and informed treatment strategies. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)

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9 pages, 347 KiB

Open AccessArticle

Gemtuzumab Ozogamicin and Stem Cell Mobilization for Autologous Stem Cell Transplantation in Favorable Risk Acute Myeloid Leukemia

by Danaë Martinez Flores, Dilara Akhoundova, Katja Seipel, Myriam Legros, Marie-Noelle Kronig, Michael Daskalakis, Ulrike Bacher and Thomas Pabst

Biomedicines 2024, 12(7), 1616; https://doi.org/10.3390/biomedicines12071616 - 19 Jul 2024

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Abstract

Gemtuzumab ozogamicin (GO), a CD33-targeting antibody drug conjugate, previously showed longer relapse-free survival when combined with induction chemotherapy in patients with favorable-risk acute myeloid leukemia (AML). In this patient population, characterized by lower relapse risk as compared to other ELN risk groups, autologous [...] Read more.

Gemtuzumab ozogamicin (GO), a CD33-targeting antibody drug conjugate, previously showed longer relapse-free survival when combined with induction chemotherapy in patients with favorable-risk acute myeloid leukemia (AML). In this patient population, characterized by lower relapse risk as compared to other ELN risk groups, autologous stem cell transplantation (ASCT) can be used as consolidation strategy. However, there are limited data on the impact of GO on the peripheral blood stem cell (PBSC) mobilization potential. We therefore retrospectively analyzed data from 54 AML patients with favorable-risk AML treated with (n = 17) or without (n = 37) GO during induction treatment. We observed no significant differences in the PBSC mobilization rate between patients treated with vs. without GO. The mobilization success in a first attempt directly following cycle 2 was 65% vs. 70% (p = 0.92); and the mobilization success in a subsequent second attempt after hematologic recovery and repeated stimulation procedure was 24% vs. 19% (p = 0.56). No significant impact on treatment outcome in terms of EFS (p = 0.31) or OS (p = 0.99) was observed. Thus, our results suggest that the addition of GO to induction regimens does not negatively impact PBSC mobilization in favorable-risk AML patients. To our best knowledge, this is the first study comparing the stem cell mobilization potential in favorable-risk AML patients treated with vs. without GO. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)

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Review

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29 pages, 1134 KiB

Open AccessReview

The Role of Epithelial-to-Mesenchymal Transition Transcription Factors (EMT-TFs) in Acute Myeloid Leukemia Progression

by Diego Cuevas, Roberto Amigo, Adolfo Agurto, Adan Andreu Heredia, Catherine Guzmán, Antonia Recabal-Beyer, Valentina González-Pecchi, Teresa Caprile, Jody J. Haigh and Carlos Farkas

Biomedicines 2024, 12(8), 1915; https://doi.org/10.3390/biomedicines12081915 - 21 Aug 2024

Cited by 2 | Viewed by 2257

Abstract

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML [...] Read more.

Acute myeloid leukemia (AML) is a diverse malignancy originating from myeloid progenitor cells, with significant genetic and clinical variability. Modern classification systems like those from the World Health Organization (WHO) and European LeukemiaNet use immunophenotyping, molecular genetics, and clinical features to categorize AML subtypes. This classification highlights crucial genetic markers such as FLT3, NPM1 mutations, and MLL-AF9 fusion, which are essential for prognosis and directing targeted therapies. The MLL-AF9 fusion protein is often linked with therapy-resistant AML, highlighting the risk of relapse due to standard chemotherapeutic regimes. In this sense, factors like the ZEB, SNAI, and TWIST gene families, known for their roles in epithelial–mesenchymal transition (EMT) and cancer metastasis, also regulate hematopoiesis and may serve as effective therapeutic targets in AML. These genes contribute to cell proliferation, differentiation, and extramedullary hematopoiesis, suggesting new possibilities for treatment. Advancing our understanding of the molecular mechanisms that promote AML, especially how the bone marrow microenvironment affects invasion and drug resistance, is crucial. This comprehensive insight into the molecular and environmental interactions in AML emphasizes the need for ongoing research and more effective treatments. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)

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23 pages, 842 KiB

Open AccessReview

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 - 7 Mar 2024

Cited by 3 | Viewed by 4727

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

Open AccessReview

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 - 7 Jan 2024

Cited by 1 | Viewed by 2743

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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11 pages, 1307 KiB

Open AccessCase Report

Blast Transformation of Chronic Myeloid Leukemia Driven by Acquisition of t(8;21)(q22;q22)/RUNX1::RUNX1T1: Selecting Optimal Treatment Based on Clinical and Molecular Findings

by Adolfo Fernández-Sánchez, Alberto Hernández-Sánchez, Cristina De Ramón, María-Carmen Chillón, María Belén Vidriales, Mónica Baile-González, Cristina-Teresa Fuentes-Morales, Magdalena Sierra-Pacho, Lucía López-Corral and Fermín Sánchez-Guijo

Biomedicines 2024, 12(10), 2339; https://doi.org/10.3390/biomedicines12102339 - 15 Oct 2024

Viewed by 1689

Abstract

The advent of tyrosine kinase inhibitors (TKIs) has changed the natural history of chronic myeloid leukemia (CML), and the transformation from the chronic phase to the blast phase (BP) is currently an uncommon situation. However, it is one of the major remaining challenges [...] Read more.

The advent of tyrosine kinase inhibitors (TKIs) has changed the natural history of chronic myeloid leukemia (CML), and the transformation from the chronic phase to the blast phase (BP) is currently an uncommon situation. However, it is one of the major remaining challenges in the management of this disease, as it is associated with dismal outcomes. We report the case of a 63-year-old woman with a history of CML with poor response to imatinib who progressed to myeloid BP-CML, driven by the acquisition of t(8;21)(q22;q22)/RUNX1::RUNX1T1. The patient received intensive chemotherapy and dasatinib, followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, she suffered an early relapse after allo-HSCT with the acquisition of the T315I mutation in ABL1. Ponatinib and azacitidine were started as salvage treatment, allowing for the achievement of complete remission with deep molecular response after five cycles. Advances in the knowledge of disease biology and clonal evolution are crucial for optimal treatment selection, which ultimately translates into better patient outcomes. Full article

(This article belongs to the Special Issue Advances in the Pathogenesis and Treatment of Acute Myeloid Leukemia)

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22 pages, 1554 KiB

Open AccessSystematic 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

Cited by 5 | Viewed by 4096

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

Open AccessCase 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

Cited by 1 | Viewed by 2210

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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