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Genetics and Epigenetics of Pediatric Leukemia
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Genetics and Epigenetics of Pediatric 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 (19 April 2021) | Viewed by 24061

Special Issue Editors

Dr. Jessica Nordlund

E-Mail Website
Guest Editor
Department of Medical Sciences and Science for Life Laboratory, Uppsala University, 751 20 Uppsala, Sweden
Interests: acute lymphoblastic leukemia; next-generation sequencing; DNA methylation; genomics; bioinformatics; machine learning
Dr. Linda Holmfeldt

E-Mail Website
Guest Editor
Department of Immunology, Genetics and Pathology, Uppsala University, 752 36 Uppsala, Sweden
Interests: acute myeloid leukemia; acute lymphoblastic leukemia; genomics; transcriptomics; DNA methylation; proteomics

Special Issue Information

Dear Colleagues,

The technological innovations over the last decade have substantially increased the utility of genomic analyses in clinical cohorts by enabling comprehensive identification of most forms of genetic variations, transcriptome profiling, and analysis of epigenomes. Such approaches have stimulated systematic studies of the genetic and epigenetic changes occurring in leukemic cells and have aided in improving diagnosis and risk classification. We are now seeing a paradigm shift where high-throughput technologies are being implemented in clinics for personalized genomic medicine in the field of pediatric leukemia.

This Special Issue welcomes submissions related to genetic, transcriptomic, epigenetic, or multi-omic aspects of leukemia biology. Preference will be given to papers that aim to build on our molecular understanding of pediatric leukemias for the purpose of developing preventive, diagnostic, or therapeutic approaches, including personalized medicine.

Dr. Jessica Nordlund
Dr. Linda Holmfeldt
Guest Editors

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. Genes 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

  • pediatric leukemia
  • acute lymphoblastic leukemia
  • acute myeloid leukemia
  • genetics, epigenetics
  • transcriptomics
  • bioinformatics
  • survival analysis
  • diagnostics
  • personalized medicine.

Published Papers (5 papers)

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Research

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16 pages, 5680 KiB  
Article
DNA Methylation Signatures Predict Cytogenetic Subtype and Outcome in Pediatric Acute Myeloid Leukemia (AML)
by Olga Krali, Josefine Palle, Christofer L. Bäcklin, Jonas Abrahamsson, Ulrika Norén-Nyström, Henrik Hasle, Kirsi Jahnukainen, Ólafur Gísli Jónsson, Randi Hovland, Birgitte Lausen, Rolf Larsson, Lars Palmqvist, Anna Staffas, Bernward Zeller and Jessica Nordlund
Genes 2021, 12(6), 895; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060895 - 10 Jun 2021
Cited by 9 | Viewed by 4089
Abstract
Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients [...] Read more.
Pediatric acute myeloid leukemia (AML) is a heterogeneous disease composed of clinically relevant subtypes defined by recurrent cytogenetic aberrations. The majority of the aberrations used in risk grouping for treatment decisions are extensively studied, but still a large proportion of pediatric AML patients remain cytogenetically undefined and would therefore benefit from additional molecular investigation. As aberrant epigenetic regulation has been widely observed during leukemogenesis, we hypothesized that DNA methylation signatures could be used to predict molecular subtypes and identify signatures with prognostic impact in AML. To study genome-wide DNA methylation, we analyzed 123 diagnostic and 19 relapse AML samples on Illumina 450k DNA methylation arrays. We designed and validated DNA methylation-based classifiers for AML cytogenetic subtype, resulting in an overall test accuracy of 91%. Furthermore, we identified methylation signatures associated with outcome in t(8;21)/RUNX1-RUNX1T1, normal karyotype, and MLL/KMT2A-rearranged subgroups (p < 0.01). Overall, these results further underscore the clinical value of DNA methylation analysis in AML. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Pediatric Leukemia)
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13 pages, 4250 KiB  
Article
Epigenetic Modification of Death Receptor Genes for TRAIL and TRAIL Resistance in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia
by Atsushi Watanabe, Kunio Miyake, Koshi Akahane, Kumiko Goi, Keiko Kagami, Hideo Yagita and Takeshi Inukai
Genes 2021, 12(6), 864; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060864 - 05 Jun 2021
Cited by 4 | Viewed by 2417
Abstract
Immunotherapies specific for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), such as anti-CD19 chimeric antigen receptor (CAR) T-cells and blinatumomab, have dramatically improved the therapeutic outcome in refractory cases. In the anti-leukemic activity of those immunotherapies, TNF-related apoptosis-inducing ligand (TRAIL) on cytotoxic T-cells plays [...] Read more.
Immunotherapies specific for B-cell precursor acute lymphoblastic leukemia (BCP-ALL), such as anti-CD19 chimeric antigen receptor (CAR) T-cells and blinatumomab, have dramatically improved the therapeutic outcome in refractory cases. In the anti-leukemic activity of those immunotherapies, TNF-related apoptosis-inducing ligand (TRAIL) on cytotoxic T-cells plays an essential role by inducing apoptosis of the target leukemia cells through its death receptors (DR4 and DR5). Since there are CpG islands in the promoter regions, hypermethylation of the DR4 and DR5 genes may be involved in resistance of leukemia cells to immunotherapies due to TRAIL-resistance. We analyzed the DR4 and DR5 methylation status in 32 BCP-ALL cell lines by sequencing their bisulfite PCR products with a next-generation sequencer. The DR4 and DR5 methylation status was significantly associated with the gene and cell-surface expression levels and the TRAIL-sensitivities. In the clinical samples at diagnosis (459 cases in the NOPHO study), both DR4 and DR5 genes were unmethylated in the majority of cases, whereas methylated in several cases with dic(9;20), MLL-rearrangement, and hypodiploidy, suggesting that evaluation of methylation status of the DR4 and DR5 genes might be clinically informative to predict efficacy of immunotherapy in certain cases with such unfavorable karyotypes. These observations provide an epigenetic rational for clinical efficacy of immunotherapy in the vast majority of BCP-ALL cases. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Pediatric Leukemia)
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15 pages, 1585 KiB  
Article
What Is Abnormal in Normal Karyotype Acute Myeloid Leukemia in Children? Analysis of the Mutational Landscape and Prognosis of the TARGET-AML Cohort
by Morten Krogh Herlin, Sara A. Yones, Eigil Kjeldsen, Linda Holmfeldt and Henrik Hasle
Genes 2021, 12(6), 792; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060792 - 21 May 2021
Cited by 5 | Viewed by 2910
Abstract
Normal karyotype acute myeloid leukemia (NK-AML) constitutes 20–25% of pediatric AML and detailed molecular analysis is essential to unravel the genetic background of this group. Using publicly available sequencing data from the TARGET-AML initiative, we investigated the mutational landscape of NK-AML in comparison [...] Read more.
Normal karyotype acute myeloid leukemia (NK-AML) constitutes 20–25% of pediatric AML and detailed molecular analysis is essential to unravel the genetic background of this group. Using publicly available sequencing data from the TARGET-AML initiative, we investigated the mutational landscape of NK-AML in comparison with abnormal karyotype AML (AK-AML). In 164 (97.6%) of 168 independent NK-AML samples, at least one somatic protein-coding mutation was identified using whole-genome or targeted capture sequencing. We identified a unique mutational landscape of NK-AML characterized by a higher prevalence of mutated CEBPA, FLT3, GATA2, NPM1, PTPN11, TET2, and WT1 and a lower prevalence of mutated KIT, KRAS, and NRAS compared with AK-AML. Mutated CEBPA often co-occurred with mutated GATA2, whereas mutated FLT3 co-occurred with mutated WT1 and NPM1. In multivariate regression analysis, we identified younger age, WBC count ≥50 × 109/L, FLT3-internal tandem duplications, and mutated WT1 as independent predictors of adverse prognosis and mutated NPM1 and GATA2 as independent predictors of favorable prognosis in NK-AML. In conclusion, NK-AML in children is characterized by a unique mutational landscape which impacts the disease outcome. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Pediatric Leukemia)
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12 pages, 1485 KiB  
Article
Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia
by Željko Antić, Stefan H. Lelieveld, Cédric G. van der Ham, Edwin Sonneveld, Peter M. Hoogerbrugge and Roland P. Kuiper
Genes 2021, 12(2), 214; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020214 - 02 Feb 2021
Cited by 5 | Viewed by 2349
Abstract
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. [...] Read more.
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. Based on mutation allele frequencies at diagnosis and subsequent relapses, we clustered mutations into groups and performed cluster-specific mutational profile analysis and de novo signature extraction. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity. The associated signatures SBS2 and SBS13 were present already at diagnosis, and although emerging mutations were lost in later relapses, the process remained active throughout disease evolution. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling ultraviolet light-driven DNA damage, and thiopurine-associated damage at first relapse. In conclusion, our data shows that investigation of mutational processes in clusters separated in time may aid in understanding the mutational mechanisms and discovery of underlying causes. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Pediatric Leukemia)
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Review

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32 pages, 1239 KiB  
Review
Cytogenetics of Pediatric Acute Myeloid Leukemia: A Review of the Current Knowledge
by Julie Quessada, Wendy Cuccuini, Paul Saultier, Marie Loosveld, Christine J. Harrison and Marina Lafage-Pochitaloff
Genes 2021, 12(6), 924; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060924 - 17 Jun 2021
Cited by 40 | Viewed by 11049
Abstract
Pediatric acute myeloid leukemia is a rare and heterogeneous disease in relation to morphology, immunophenotyping, germline and somatic cytogenetic and genetic abnormalities. Over recent decades, outcomes have greatly improved, although survival rates remain around 70% and the relapse rate is high, at around [...] Read more.
Pediatric acute myeloid leukemia is a rare and heterogeneous disease in relation to morphology, immunophenotyping, germline and somatic cytogenetic and genetic abnormalities. Over recent decades, outcomes have greatly improved, although survival rates remain around 70% and the relapse rate is high, at around 30%. Cytogenetics is an important factor for diagnosis and indication of prognosis. The main cytogenetic abnormalities are referenced in the current WHO classification of acute myeloid leukemia, where there is an indication for risk-adapted therapy. The aim of this article is to provide an updated review of cytogenetics in pediatric AML, describing well-known WHO entities, as well as new subgroups and germline mutations with therapeutic implications. We describe the main chromosomal abnormalities, their frequency according to age and AML subtypes, and their prognostic relevance within current therapeutic protocols. We focus on de novo AML and on cytogenetic diagnosis, including the practical difficulties encountered, based on the most recent hematological and cytogenetic recommendations. Full article
(This article belongs to the Special Issue Genetics and Epigenetics of Pediatric Leukemia)
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