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Molecular Research on Acute Myeloid Leukemia (AML) Volume II
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Molecular Research on Acute Myeloid Leukemia (AML) Volume II

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

Deadline for manuscript submissions: closed (31 August 2024) | Viewed by 12069

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

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Keywords

  • acute myeloid leukemia
  • molecular pathogenesis
  • novel AML therapies
  • AML clonal evolution
  • epigenetic alterations
  • multi-omics
  • precision medicine
  • leukemia stem cell

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Published Papers (7 papers)

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Research

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14 pages, 1644 KiB  
Article
Characteristics and Prognosis of “Acute Promyelocytic Leukemia-like” Nucleophosmin-1-Mutated Acute Myeloid Leukemia in a Retrospective Patient Cohort
by Vasiliki Papadopoulou, Giulia Schiavini, Gregoire Stalder, Valentin Basset, Jacqueline Schoumans, Mitja Nabergoj and Muriel Schaller
Biomedicines 2024, 12(10), 2282; https://doi.org/10.3390/biomedicines12102282 - 9 Oct 2024
Viewed by 742
Abstract
Background: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases. It is characterized by CD34 negativity, which suggests a relatively differentiated state of the bulk of leukemic blasts. Notably, a significant subset of NPM1-mutated AML cases [...] Read more.
Background: AML with NPM1 mutation is the largest subcategory of AML, representing about 35% of AML cases. It is characterized by CD34 negativity, which suggests a relatively differentiated state of the bulk of leukemic blasts. Notably, a significant subset of NPM1-mutated AML cases also exhibit HLA-DR negativity, classifying them as “double-negative”, and mimicking, therefore, the CD34− HLA-DR− immunophenotype of acute promyelocytic leukemia (APL). Objectives: This study focuses on the “acute promyelocytic leukemia-like” (“APL-like”) subset of NPM1-mutated AML, which can be challenging to distinguish from APL at presentation, prior to confirming RARa translocations. We aim to investigate the hematologic and immunophenotypic parameters that may aid to its distinction from APL. Additionally, we explore differences in genetic profile and prognosis between “APL-like” and “non-APL-like” NPM1-mutated AML cases. Methods: We conducted a retrospective evaluation of 77 NPM1-mutated AML cases and 28 APL cases. Results: Morphological characteristics, hematologic parameters (such as DD/WBC and PT/WBC), and specific immunophenotypic markers (including SSC, CD64, and CD4) can assist in the early distinction of “APL-like” NPM1-mutated AML from APL. Regarding differences in genetic profiles and outcomes between “APL-like” and non-“APL-like” NPM1-mutated AML cases, we observed a significantly higher incidence of IDH1/2 /TET2 mutations, along with a significantly lower incidence of DNMT3A mutations in the “APL-like” subset compared to the non-“APL-like” subset. The frequency of Ras-pathway and FLT3 mutations did not differ between these last two groups, nor did their prognoses. Conclusions: Our findings contribute to a comprehensive characterization of NPM1-mutated AML, enhancing diagnostic accuracy and aiding in the detailed classification of the disease. This information may potentially guide targeted therapies or differentiation-based treatment strategies. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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17 pages, 3578 KiB  
Article
Hotspot DNA Methyltransferase 3A (DNMT3A) and Isocitrate Dehydrogenase 1 and 2 (IDH1/2) Mutations in Acute Myeloid Leukemia and Their Relevance as Targets for Immunotherapy
by Nadine E. Struckman, Rob C. M. de Jong, M. Willy Honders, Sophie-Anne I. Smith, Dyantha I. van der Lee, Georgia Koutsoumpli, Arnoud H. de Ru, Jan-Henrik Mikesch, Peter A. van Veelen, J. H. Frederik Falkenburg and Marieke Griffioen
Biomedicines 2024, 12(5), 1086; https://doi.org/10.3390/biomedicines12051086 - 14 May 2024
Viewed by 1326
Abstract
DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 1 and 2 (IDH1/2) are genes involved in epigenetic regulation, each mutated in 7–23% of patients with acute myeloid leukemia. Here, we investigated whether hotspot mutations in these genes encode neoantigens that [...] Read more.
DNA methyltransferase 3A (DNMT3A) and isocitrate dehydrogenase 1 and 2 (IDH1/2) are genes involved in epigenetic regulation, each mutated in 7–23% of patients with acute myeloid leukemia. Here, we investigated whether hotspot mutations in these genes encode neoantigens that can be targeted by immunotherapy. Five human B-lymphoblastoid cell lines expressing common HLA class I alleles were transduced with a minigene construct containing mutations that often occur in DNMT3A or IDH1/2. From these minigene-transduced cell lines, peptides were eluted from HLA class I alleles and analyzed using tandem mass spectrometry. The resulting data are available via ProteomeXchange under the identifier PXD050560. Mass spectrometry revealed an HLA-A*01:01-binding DNMT3AR882H peptide and an HLA-B*07:02-binding IDH2R140Q peptide as potential neoantigens. For these neopeptides, peptide–HLA tetramers were produced to search for specific T-cells in healthy individuals. Various T-cell clones were isolated showing specific reactivity against cell lines transduced with full-length DNMT3AR882H or IDH2R140Q genes, while cell lines transduced with wildtype genes were not recognized. One T-cell clone for DNMT3AR882H also reacted against patient-derived acute myeloid leukemia cells with the mutation, while patient samples without the mutation were not recognized, thereby validating the surface presentation of a DNMT3AR882H neoantigen that can potentially be targeted in acute myeloid leukemia via immunotherapy. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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11 pages, 1153 KiB  
Article
Blast-Derived Small Extracellular Vesicles in the Plasma of Patients with Acute Myeloid Leukemia Predict Responses to Chemotherapy
by Michael Boyiadzis, Chang-Sook Hong, Saigopalakrishna Yerneni, Annie Im, Brenda Diergaarde and Theresa L. Whiteside
Biomedicines 2023, 11(12), 3236; https://doi.org/10.3390/biomedicines11123236 - 7 Dec 2023
Viewed by 1433
Abstract
The small extracellular vesicles (sEV) accumulating in acute myeloid leukemia (AML) patients’ plasma are mixtures of vesicles produced by leukemic and non-malignant cells. sEV originating from leukemia blasts could serve as potential non-invasive biomarkers of AML response to therapy. To isolate blast-derived sEV [...] Read more.
The small extracellular vesicles (sEV) accumulating in acute myeloid leukemia (AML) patients’ plasma are mixtures of vesicles produced by leukemic and non-malignant cells. sEV originating from leukemia blasts could serve as potential non-invasive biomarkers of AML response to therapy. To isolate blast-derived sEV from patients’ plasma, we developed a bioprinted microarray-based immunoassay using monoclonal antibodies (mAbs) specific for leukemia-associated antigens (LAAs) and mAbs specific for a mix of tetraspanins (CD9, CD63, and CD81). We determined the proportion of LAA+ sEV relative to total plasma sEV (the LAA+/total sEV ratio) in serially collected samples of newly diagnosed AML patients prior to, during, and after chemotherapy. At AML diagnosis, the LAA+/total sEV ratio was significantly higher in patients than in healthy donors (HDs). In patients who achieved complete remission (CR) after induction chemotherapy, the LAA+/total sEV ratios significantly decreased after each chemotherapy cycle to levels seen in HDs. In contrast, the LAA+/total sEV ratios in AML patients with persistent leukemia after therapy remained elevated during and after therapy, as did the percentage of leukemic blasts in these patients’ bone marrows. The LAA+/total sEV ratio emerges as a promising non-invasive biomarker of leukemia response to therapy. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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Review

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26 pages, 884 KiB  
Review
Molecular Features and Treatment Paradigms of Acute Myeloid Leukemia
by Mihir Shukla, Maher Abdul-Hay and Jun H. Choi
Biomedicines 2024, 12(8), 1768; https://doi.org/10.3390/biomedicines12081768 - 6 Aug 2024
Cited by 1 | Viewed by 1993
Abstract
Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation. More recently, with the use of next-generation [...] Read more.
Acute myeloid leukemia (AML) is a common hematologic malignancy that is considered to be a disease of aging, and traditionally has been treated with induction chemotherapy, followed by consolidation chemotherapy and/or allogenic hematopoietic stem cell transplantation. More recently, with the use of next-generation sequencing and access to molecular information, targeted molecular approaches to the treatment of AML have been adopted. Molecular targeting is gaining prominence, as AML mostly afflicts the elderly population, who often cannot tolerate traditional chemotherapy. Understanding molecular changes at the gene level is also important for accurate disease classification, risk stratification, and prognosis, allowing for more personalized medicine. Some mutations are well studied and have an established gene-specific therapy, including FLT3 and IDH1/2, while others are being investigated in clinical trials. However, data on most known mutations in AML are still minimal and therapeutic studies are in pre-clinical stages, highlighting the importance of further research and elucidation of the pathophysiology involving these genes. In this review, we aim to highlight the key molecular alterations and chromosomal changes that characterize AML, with a focus on pathophysiology, presently available treatment approaches, and future therapeutic options. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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18 pages, 1447 KiB  
Review
Therapy-Related Myeloid Neoplasm: Biology and Mechanistic Aspects of Malignant Progression
by Serena Travaglini, Massimiliano Marinoni, Valeria Visconte and Luca Guarnera
Biomedicines 2024, 12(5), 1054; https://doi.org/10.3390/biomedicines12051054 - 10 May 2024
Viewed by 1822
Abstract
Therapy-related myeloid neoplasms (t-MN) arise after a documented history of chemo/radiotherapy as treatment for an unrelated condition and account for 10–20% of myelodysplastic syndromes and acute myeloid leukemia. T-MN are characterized by a specific genetic signature, aggressive features and dismal prognosis. The nomenclature [...] Read more.
Therapy-related myeloid neoplasms (t-MN) arise after a documented history of chemo/radiotherapy as treatment for an unrelated condition and account for 10–20% of myelodysplastic syndromes and acute myeloid leukemia. T-MN are characterized by a specific genetic signature, aggressive features and dismal prognosis. The nomenclature and the subsets of these conditions have changed frequently over time, and despite the fact that, in the last classification, they lost their autonomous entity status and became disease qualifiers, the recognition of this feature remains of major importance. Furthermore, in recent years, extensive studies focusing on clonal hematopoiesis and germline variants shed light on the mechanisms of positive pressure underpinning the rise of driver gene mutations in t-MN. In this manuscript, we aim to review the evolution of defining criteria and characteristics of t-MN from a clinical and biological perspective, the advances in mechanistic aspects of malignant progression and the challenges in prevention and management. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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26 pages, 648 KiB  
Review
Transplant Eligible and Ineligible Elderly Patients with AML—A Genomic Approach and Next Generation Questions
by Paul Sackstein, Alexis Williams, Rachel Zemel, Jennifer A. Marks, Anne S. Renteria and Gustavo Rivero
Biomedicines 2024, 12(5), 975; https://doi.org/10.3390/biomedicines12050975 - 29 Apr 2024
Viewed by 1724
Abstract
The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, [...] Read more.
The management of elderly patients diagnosed with acute myelogenous leukemia (AML) is complicated by high relapse risk and comorbidities that often preclude access to allogeneic hematopoietic cellular transplantation (allo-HCT). In recent years, fast-paced FDA drug approval has reshaped the therapeutic landscape, with modest, albeit promising improvement in survival. Still, AML outcomes in elderly patients remain unacceptably unfavorable highlighting the need for better understanding of disease biology and tailored strategies. In this review, we discuss recent modifications suggested by European Leukemia Network 2022 (ELN-2022) risk stratification and review recent aging cell biology advances with the discussion of four AML cases. While an older age, >60 years, does not constitute an absolute contraindication for allo-HCT, the careful patient selection based on a detailed and multidisciplinary risk stratification cannot be overemphasized. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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Other

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11 pages, 3038 KiB  
Case Report
Single-Cell DNA Sequencing and Immunophenotypic Profiling to Track Clonal Evolution in an Acute Myeloid Leukemia Patient
by María García-Álvarez, Ana Yeguas, Cristina Jiménez, Alejandro Medina-Herrera, Verónica González-Calle, Montserrat Hernández-Ruano, Rebeca Maldonado, Irene Aires, Cristina Casquero, Inmaculada Sánchez-Villares, Ana Balanzategui, María Eugenia Sarasquete, Miguel Alcoceba, María Belén Vidriales, Marcos González-Díaz, Ramón García-Sanz and María Carmen Chillón
Biomedicines 2024, 12(1), 66; https://doi.org/10.3390/biomedicines12010066 - 27 Dec 2023
Viewed by 1772
Abstract
Single-cell DNA sequencing can address the sequence of somatic genetic events during myeloid transformation in relapsed acute myeloid leukemia (AML). We present an NPM1-mutated AML patient with an initial low ratio of FLT3-ITD (low-risk ELN-2017), treated with midostaurin combined with standard [...] Read more.
Single-cell DNA sequencing can address the sequence of somatic genetic events during myeloid transformation in relapsed acute myeloid leukemia (AML). We present an NPM1-mutated AML patient with an initial low ratio of FLT3-ITD (low-risk ELN-2017), treated with midostaurin combined with standard chemotherapy as front-line treatment, and with salvage therapy plus gilteritinib following allogenic stem cell transplantation after relapse. Simultaneous single-cell DNA sequencing and cell-surface immunophenotyping was used in diagnostic and relapse samples to understand the clinical scenario of this patient and to reconstruct the clonal composition of both tumors. Four independent clones were present before treatment: DNMT3A/DNMT3A/NPM1 (63.9%), DNMT3A/DNMT3A (13.9%), DNMT3A/DNMT3A/NPM1/FLT3 (13.8%), as well as a wild-type clone (8.3%), but only the minor clone with FLT3-ITD survived and expanded after therapy, being the most represented one (58.6%) at relapse. FLT3-ITD was subclonal and was found only in the myeloid blast population (CD38/CD117/CD123). Our study shows the usefulness of this approach to reveal the clonal architecture of the leukemia and the identification of small subclones at diagnosis and relapse that may explain how the neoplastic cells can escape from the activity of different treatments in a stepwise process that impedes the disease cure despite different stages of complete remission. Full article
(This article belongs to the Special Issue Molecular Research on Acute Myeloid Leukemia (AML) Volume II)
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