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Genetics and Genomics of Acute Myeloid Leukemia
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Genetics and Genomics of Acute Myeloid Leukemia

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (1 May 2020) | Viewed by 32007

Special Issue Editors

Dr. Nicholas J. Short

E-Mail Website
Guest Editor
Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Interests: acute lymphoblastic leukemia; acute myeloid leukemia; measurable residual disease
Special Issues, Collections and Topics in MDPI journals
Dr. Rashmi Kanagal-Shamanna

E-Mail Website
Guest Editor
University of Texas MD Anderson Cancer Center, Houston, TX, USA

Special Issue Information

Dear Colleagues,

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy that is rapidly fatal without prompt and effective therapy. The disease phenotype and outcomes of patients with AML are highly heterogeneous, and large-scale genomic studies have uncovered a number of recurrent mutations that impact disease biology, response to therapy, and risk of relapse following conventional therapies. These genomic alterations have been incorporated into consensus risk stratification guidelines and inform decisions for post-remission allogeneic stem cell transplantation, which is recommended for patients at high risk of relapse based on adverse-risk cytogenetics or genomic features. Small molecular inhibitors have also been developed for some of these mutations (e.g., FLT3, IDH1, and IDH2 inhibitors) and have led to improved outcomes for patients whose leukemia harbors these alterations. However, despite the immense progress that has been made in understanding the genomic landscape of AML and incorporating these discoveries into clinical practice, the long-term outcome of AML is still poor for most disease subtypes. Intense research is ongoing to better understand the ways in which genetic alterations impact pathogenesis, disease biology, and clinical outcomes, with the ultimate goal of developing novel, personalized therapeutic strategies for patients with AML.

In this Special Issue of Genes, we extend an invitation for reviews on the current state of the genetics and genomics of AML.

Dr. Nicholas J. Short
Dr. Rashmi Kanagal-Shamanna
Guest Editors

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Keywords

  • Acute myeloid leukemia
  • Genomics
  • Molecular testing
  • Pathogenesis
  • Pathobiology
  • Prognosis
  • Risk stratification
  • Outcomes
  • Targeted therapy
  • Personalized therapy

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Published Papers (5 papers)

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Research

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5 pages, 654 KiB  
Communication
Bone Marrow Clonogenic Myeloid Progenitors from NPM1-Mutated AML Patients Do Not Harbor the NPM1 Mutation: Implication for the Cell-Of-Origin of NPM1+ AML
by Rafael Diaz de la Guardia, Laura González-Silva, Belén López-Millán, Juan José Rodríguez-Sevilla, Matteo L. Baroni, Clara Bueno, Eduardo Anguita, Susana Vives, Laura Palomo, Helene Lapillonne, Ignacio Varela and Pablo Menendez
Genes 2020, 11(1), 73; https://doi.org/10.3390/genes11010073 - 9 Jan 2020
Cited by 2 | Viewed by 3135
Abstract
The cell-of-origin of NPM1- and FLT3-mutated acute myeloid leukemia (AML) is still a matter of debate. Here, we combined in vitro clonogenic assays with targeted sequencing to gain further insights into the cell-of-origin of NPM1 and FLT3-ITD-mutated AML in diagnostic bone [...] Read more.
The cell-of-origin of NPM1- and FLT3-mutated acute myeloid leukemia (AML) is still a matter of debate. Here, we combined in vitro clonogenic assays with targeted sequencing to gain further insights into the cell-of-origin of NPM1 and FLT3-ITD-mutated AML in diagnostic bone marrow (BM) from nine NPM1+/FLT3-ITD (+/−) AMLs. We reasoned that individually plucked colony forming units (CFUs) are clonal and reflect the progeny of a single stem/progenitor cell. NPM1 and FLT3-ITD mutations seen in the diagnostic blasts were found in only 2/95 and 1/57 individually plucked CFUs, suggesting that BM clonogenic myeloid progenitors in NPM1-mutated and NPM1/FLT3-ITD-mutated AML patients do not harbor such molecular lesions. This supports previous studies on NPM1 mutations as secondary mutations in AML, likely acquired in an expanded pool of committed myeloid progenitors, perhaps CD34−, in line with the CD34−/low phenotype of NPM1-mutated AMLs. This study has important implications on the cell-of-origin of NPM1+ AML, and reinforces that therapeutic targeting of either NPM1 or FLT3-ITD mutations might only have a transient clinical benefit in debulking the leukemia, but is unlikely to be curative since will not target the AML-initiating/preleukemic cells. The absence of NPM1 and FLT3-ITD mutations in normal clonogenic myeloid progenitors is in line with their absence in clonal hematopoiesis of indeterminate potential. Full article
(This article belongs to the Special Issue Genetics and Genomics of Acute Myeloid Leukemia)
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16 pages, 2111 KiB  
Article
Nanopore Targeted Sequencing for Rapid Gene Mutations Detection in Acute Myeloid Leukemia
by Cosimo Cumbo, Crescenzio Francesco Minervini, Paola Orsini, Luisa Anelli, Antonella Zagaria, Angela Minervini, Nicoletta Coccaro, Luciana Impera, Giuseppina Tota, Elisa Parciante, Maria Rosa Conserva, Orietta Spinelli, Alessandro Rambaldi, Giorgina Specchia and Francesco Albano
Genes 2019, 10(12), 1026; https://doi.org/10.3390/genes10121026 - 9 Dec 2019
Cited by 27 | Viewed by 7244
Abstract
Acute myeloid leukemia (AML) clinical settings cannot do without molecular testing to confirm or rule out predictive biomarkers for prognostic stratification, in order to initiate or withhold targeted therapy. Next generation sequencing offers the advantage of the simultaneous investigation of numerous genes, but [...] Read more.
Acute myeloid leukemia (AML) clinical settings cannot do without molecular testing to confirm or rule out predictive biomarkers for prognostic stratification, in order to initiate or withhold targeted therapy. Next generation sequencing offers the advantage of the simultaneous investigation of numerous genes, but these methods remain expensive and time consuming. In this context, we present a nanopore-based assay for rapid (24 h) sequencing of six genes (NPM1, FLT3, CEBPA, TP53, IDH1 and IDH2) that are recurrently mutated in AML. The study included 22 AML patients at diagnosis; all data were compared with the results of S5 sequencing, and discordant variants were validated by Sanger sequencing. Nanopore approach showed substantial advantages in terms of speed and low cost. Furthermore, the ability to generate long reads allows a more accurate detection of longer FLT3 internal tandem duplications and phasing double CEBPA mutations. In conclusion, we propose a cheap, rapid workflow that can potentially enable all basic molecular biology laboratories to perform detailed targeted gene sequencing analysis in AML patients, in order to define their prognosis and the appropriate treatment. Full article
(This article belongs to the Special Issue Genetics and Genomics of Acute Myeloid Leukemia)
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Review

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13 pages, 234 KiB  
Review
AML with Myelodysplasia-Related Changes: Development, Challenges, and Treatment Advances
by Kristin L. Koenig, Kieran D. Sahasrabudhe, Audrey M. Sigmund and Bhavana Bhatnagar
Genes 2020, 11(8), 845; https://doi.org/10.3390/genes11080845 - 24 Jul 2020
Cited by 33 | Viewed by 7528
Abstract
Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25–34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy [...] Read more.
Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is a distinct biologic subtype of AML that represents 25–34% of all AML diagnoses and associates with especially inferior outcomes compared to non-MRC AML. Typically, patients with AML-MRC experience low remission rates following intensive chemotherapy and a median overall survival of merely 9–12 months. In light of these discouraging outcomes, it has become evident that more effective therapies are needed for patients with AML-MRC. Liposomal daunorubicin–cytarabine (CPX-351) was approved in 2017 for adults with newly diagnosed AML-MRC and those with therapy-related AML (t-AML), and remains the only therapy specifically approved for this patient population. Other studies have also demonstrated the efficacy of the hypomethylating agent (HMA) azacitidine as upfront therapy for AML-MRC patients, which, to date, is the most common treatment employed for patients unable to tolerate the more intensive CPX-351. HMAs and venetoclax combinations have also been evaluated, but additional studies utilizing these agents in this specific subgroup are needed before conclusions regarding their role in the therapeutic armamentarium of AML-MRC patients can be reached. Currently, many studies are ongoing in attempts to further improve outcomes in this historically ill-fated patient group. Full article
(This article belongs to the Special Issue Genetics and Genomics of Acute Myeloid Leukemia)
27 pages, 759 KiB  
Review
Genetic and Genomic Landscape of Secondary and Therapy-Related Acute Myeloid Leukemia
by Alexandra Higgins and Mithun Vinod Shah
Genes 2020, 11(7), 749; https://doi.org/10.3390/genes11070749 - 6 Jul 2020
Cited by 30 | Viewed by 5030
Abstract
A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them [...] Read more.
A subset of acute myeloid leukemia (AML) arises either from an antecedent myeloid malignancy (secondary AML, sAML) or as a complication of DNA-damaging therapy for other cancers (therapy-related myeloid neoplasm, t-MN). These secondary leukemias have unique biological and clinical features that distinguish them from de novo AML. Over the last decade, molecular techniques have unraveled the complex subclonal architecture of sAML and t-MN. In this review, we compare and contrast biological and clinical features of de novo AML with sAML and t-MN. We discuss the role of genetic mutations, including those involved in RNA splicing, epigenetic modification, tumor suppression, transcription regulation, and cell signaling, in the pathogenesis of secondary leukemia. We also discuss clonal hematopoiesis in otherwise healthy individuals, as well as in the context of another malignancy, and how it challenges the conventional notion of sAML/t-MN. We conclude by summarizing the current and emerging treatment strategies, including allogenic transplant, in these complex scenarios. Full article
(This article belongs to the Special Issue Genetics and Genomics of Acute Myeloid Leukemia)
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16 pages, 913 KiB  
Review
Nucleophosmin 1 Mutations in Acute Myeloid Leukemia
by Jabra Zarka, Nicholas J. Short, Rashmi Kanagal-Shamanna and Ghayas C. Issa
Genes 2020, 11(6), 649; https://doi.org/10.3390/genes11060649 - 12 Jun 2020
Cited by 37 | Viewed by 8402
Abstract
Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These [...] Read more.
Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations. Full article
(This article belongs to the Special Issue Genetics and Genomics of Acute Myeloid Leukemia)
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