Submit to Biomedicines Review for Biomedicines Propose a Special Issue

Journal Browser

Molecular Research on Acute Myeloid Leukemia (AML)

Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 12954

Share This Special Issue

Special Issue Editor

Dr. Michele Gottardi

E-Mail Website
Guest Editor

Onco Hematology, Department of Oncology, Veneto Institute of Oncology IOV, IRCCS, 31033 Padua, Italy
Interests: AML; core binding factor AML; novel agents; bone marrow microenviroment; HSCT
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Acute myeloid leukemia (AML) is an extremely heterogeneous disease that originates from an aberrant proliferation and/or block in the normal differentiation of hematopoietic cells. Remarkable advances have been made during the last decade to understand the AML genome, both at disease diagnosis and relapse and to explain how genetic alterations might influence the distinct biological subgroups and their role in clonal evolution. The development of novel innovative technologies has not only allowed us to detect the genetic alterations as early as possible, but also to understand the molecular pathogenesis of AML, ultimately opening the door to personalized therapy for specific AML patient populations, with promising results. Finally, understanding the metabolic consequences of specific driver genetic lesions sounds particularly attractive for identifying future metabolic-targeted therapies with the aim of overcoming AML refractoriness. In the present Special Issue, we invite authors to submit original research papers and reviews on how deciphering the molecular mechanisms underlying the pathogenesis of the disease could change our current diagnostic and therapeutic approach in treating AML.

Dr. Michele Gottardi
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
molecular pathogenesis
novel AML therapies
AML clonal evolution
epigenetic alterations
multi-omics
precision medicine
leukemia stem cell

Published Papers (5 papers)

Download All Papers

Research

Jump to: Review

14 pages, 2215 KiB

Open AccessArticle

Systemic Optimization of Gene Electrotransfer Protocol Using Hard-to-Transfect UT-7 Cell Line as a Model

by Roberta Vadeikienė, Baltramiejus Jakštys, Rasa Ugenskienė, Saulius Šatkauskas and Elona Juozaitytė

Biomedicines 2022, 10(11), 2687; https://doi.org/10.3390/biomedicines10112687 - 24 Oct 2022

Viewed by 1393

Abstract

Non-adherent cells are difficult to transfect with chemical-mediated delivery methods. Electroporation is an attractive strategy to transfer the molecules of interest into suspension cells. Care must be taken with the viability of the transfected cells since parameters, which increase cell membrane permeability, subsequently increase transfection efficiency, leading to higher cell death indices. We intended to evaluate the distribution of hard-to-transfect UT-7 cells among different subpopulations: transfected/viable, untransfected/viable, transfected/dead, and untransfected/dead populations, for a better understanding of the relation between gene electrotransfer efficacy and cell death. The following electroporation parameters were tested: pulse strength, duration, plasmid DNA concentration, and ZnSO₄ as DNase inhibitor. BTX T820 square-wave generator was used, and 48 h after electroporation, cells were observed for viability and fluorescence analysis. Increasing pulse strength correlated directly with an increased ratio of pEGFP-positive cells and inversely with cell viability. The best results, representing 21% pEGFP positive/viable cells, were obtained after EP with 1 HV 1400 V/cm pulse of 250 µs duration using 200 µg/mL plasmid concentration. Results demonstrated that plasmid concentration played the most significant role in pEGFP electrotransfer into UT-7 cells. These results can represent a relevant improvement of gene electrotransfer to obtain genetically modified suspension cells for further downstream experiments. Full article

(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML))

► Show Figures

Figure 1

15 pages, 1585 KiB

Open AccessArticle

Molecular Measurable Residual Disease Assessment before Hematopoietic Stem Cell Transplantation in Pediatric Acute Myeloid Leukemia Patients: A Retrospective Study by the I-BFM Study Group

by Maddalena Benetton, Pietro Merli, Christiane Walter, Maria Hansen, Ambra Da Ros, Katia Polato, Claudia Tregnago, Jonas Abrahamsson, Luisa Strocchio, Edwin Sonneveld, Linda Fogelstrand, Nils Von Neuhoff, Dirk Reinhardt, Henrik Hasle, Martina Pigazzi and Franco Locatelli

Biomedicines 2022, 10(7), 1530; https://doi.org/10.3390/biomedicines10071530 - 28 Jun 2022

Cited by 1 | Viewed by 2573

Abstract

Hematopoietic stem cell transplantation (HSCT) is a curative post-remission treatment in patients with acute myeloid leukemia (AML), but relapse after transplant is still a challenging event. In recent year, several studies have investigated the molecular minimal residual disease (qPCR-MRD) as a predictor of relapse, but the lack of standardized protocols, cut-offs, and timepoints, especially in the pediatric setting, has prevented its use in several settings, including before HSCT. Here, we propose the first collaborative retrospective I-BFM-AML study assessing qPCR-MRD values in pretransplant bone marrow samples of 112 patients with a diagnosis of AML harboring t(8;21)(q22; q22)RUNX1::RUNX1T1, or inv(16)(p13q22)CBFB::MYH11, or t(9;11)(p21;q23)KMT2A::MLLT3, or FLT3-ITD genetic markers. We calculated an ROC cut-off of 2.1 × 10⁻⁴ that revealed significantly increased OS (83.7% versus 57.1%) and EFS (80.2% versus 52.9%) for those patients with lower qPCR-MRD values. Then, we partitioned patients into three qPCR-MRD groups by combining two different thresholds, 2.1 × 10⁻⁴ and one lower cut-off of 1 × 10⁻², and stratified patients into low-, intermediate-, and high-risk groups. We found that the 5-year OS (83.7%, 68.6%, and 39.2%, respectively) and relapse-free survival (89.2%, 73.9%, and 67.9%, respectively) were significantly different independent of the genetic lesion, conditioning regimen, donor, and stem cell source. These data support the PCR-based approach playing a clinical relevance in AML transplant management. Full article

(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML))

► Show Figures

Graphical abstract

16 pages, 3685 KiB

Open AccessArticle

Targeting TKI-Activated NFKB2-MIF/CXCLs-CXCR2 Signaling Pathways in FLT3 Mutated Acute Myeloid Leukemia Reduced Blast Viability

by Huynh Cao, Verena Tadros, Benjamin Hiramoto, Kevin Leeper, Christopher Hino, Jeffrey Xiao, Bryan Pham, Do Hyun Kim, Mark E. Reeves, Chien-Shing Chen, Jiang F. Zhong, Ke K. Zhang, Linglin Xie, Samiksha Wasnik, David J. Baylink and Yi Xu

Biomedicines 2022, 10(5), 1038; https://doi.org/10.3390/biomedicines10051038 - 30 Apr 2022

Cited by 10 | Viewed by 2429

Abstract

Disease relapse is a common cause of treatment failure in FMS-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). In this study, to identify therapeutic targets responsible for the survival and proliferation of leukemic cells (blasts) with FLT3 mutations after gilteritinib (GILT, a 2nd generation tyrosine kinase inhibitor (TKI)) treatment, we performed proteomic screening of cytokine release and in vitro/ex vivo studies to investigate their associated signaling pathways and transcriptional regulation. Here, we report that macrophage migration inhibition factor (MIF) was significantly increased in the supernatant of GILT-treated blasts when compared to untreated controls. Additionally, the GILT-treated blasts that survived were found to exhibit higher expressions of the CXCR2 gene and protein, a common receptor for MIF and pro-inflammatory cytokines. The supplementation of exogenous MIF to GILT-treated blasts revealed a group of CD44High+ cells that might be responsible for the relapse. Furthermore, we identified the highly activated non-classical NFKB2 pathway after GILT-treatment. The siRNA transient knockdown of NFKB2 significantly reduced the gene expressions of MIF, CXCR2, and CXCL5. Finally, treatments of AML patient samples ex vivo demonstrated that the combination of a pharmaceutical inhibitor of the NFKB family and GILT can effectively suppress primary blasts’ secretion of tumor-promoting cytokines, such as CXCL1/5/8. In summary, we provide the first evidence that targeting treatment-activated compensatory pathways, such as the NFKB2-MIF/CXCLs-CXCR2 axis could be a novel therapeutic strategy to overcome TKI-resistance and effectively treat AML patients with FLT3 mutations. Full article

(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML))

► Show Figures

Figure 1

Review

Jump to: Research

19 pages, 2136 KiB

Open AccessReview

Measurable Residual Disease and Clonal Evolution in Acute Myeloid Leukemia from Diagnosis to Post-Transplant Follow-Up: The Role of Next-Generation Sequencing

by Alessandra Sperotto, Maria Teresa Bochicchio, Giorgia Simonetti, Francesco Buccisano, Jacopo Peccatori, Simona Piemontese, Elisabetta Calistri, Giulia Ciotti, Elisabetta Pierdomenico, Roberta De Marchi, Fabio Ciceri and Michele Gottardi

Biomedicines 2023, 11(2), 359; https://doi.org/10.3390/biomedicines11020359 - 26 Jan 2023

Viewed by 2080

Abstract

It has now been ascertained that acute myeloid leukemias—as in most type of cancers—are mixtures of various subclones, evolving by acquiring additional somatic mutations over the course of the disease. The complexity of leukemia clone architecture and the phenotypic and/or genotypic drifts that can occur during treatment explain why more than 50% of patients—in hematological remission—could relapse. Moreover, the complexity and heterogeneity of clone architecture represent a hindrance for monitoring measurable residual disease, as not all minimal residual disease monitoring methods are able to detect genetic mutations arising during treatment. Unlike with chemotherapy, which imparts a relatively short duration of selective pressure on acute myeloid leukemia clonal architecture, the immunological effect related to allogeneic hematopoietic stem cell transplant is prolonged over time and must be overcome for relapse to occur. This means that not all molecular abnormalities detected after transplant always imply inevitable relapse. Therefore, transplant represents a critical setting where a measurable residual disease-based strategy, performed during post-transplant follow-up by highly sensitive methods such as next-generation sequencing, could optimize and improve treatment outcome. The purpose of our review is to provide an overview of the role of next-generation sequencing in monitoring both measurable residual disease and clonal evolution in acute myeloid leukemia patients during the entire course of the disease, with special focus on the transplant phase. Full article

(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML))

► Show Figures

Figure 1

16 pages, 1398 KiB

Open AccessReview

Targeting of Mevalonate-Isoprenoid Pathway in Acute Myeloid Leukemia Cells by Bisphosphonate Drugs

by Emanuela Chiarella, Clelia Nisticò, Anna Di Vito, Helen Linda Morrone and Maria Mesuraca

Biomedicines 2022, 10(5), 1146; https://doi.org/10.3390/biomedicines10051146 - 16 May 2022

Cited by 12 | Viewed by 3419

Abstract

Metabolic reprogramming represents a hallmark of tumorigenesis to sustain survival in harsh conditions, rapid growth and metastasis in order to resist to cancer therapies. These metabolic alterations involve glucose metabolism, known as the Warburg effect, increased glutaminolysis and enhanced amino acid and lipid metabolism, especially the cholesterol biosynthesis pathway known as the mevalonate pathway and these are upregulated in several cancer types, including acute myeloid leukemia (AML). In particular, it was demonstrated that the mevalonate pathway has a pivotal role in cellular transformation. Therefore, targeting this biochemical process with drugs such as statins represents a promising therapeutic strategy to be combined with other anticancer treatments. In the last decade, several studies have revealed that amino-bisphosphonates (BP), primarily used for bone fragility disorders, also exhibit potential anti-cancer activity in leukemic cells, as well as in patients with symptomatic multiple myeloma. Indeed, these compounds inhibit the farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway, reducing isoprenoid formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. This, in turn, inhibits the prenylation of small Guanosine Triphosphate-binding proteins, such as Ras, Rho, Rac, Rab, which are essential for regulating cell survival membrane ruffling and trafficking, interfering with cancer key signaling events involved in clonal expansion and maturation block of progenitor cells in myeloid hematological malignancies. Thus, in this review, we discuss the recent advancements about bisphosphonates’ effects, especially zoledronate, analyzing the biochemical mechanisms and anti-tumor effects on AML model systems. Future studies will be oriented to investigate the clinical relevance and significance of BP treatment in AML, representing an attractive therapeutic strategy that could be integrated into chemotherapy. Full article

(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML))

► Show Figures