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Cancers
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Genomic Alterations of Leukemia
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Genomic Alterations of Leukemia

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 20016

Special Issue Editor

Dr. Ilaria Iacobucci

E-Mail Website
Guest Editor
Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Interests: acute myeloid leukemia; acute lymphoblastic leukemia; genomics; functional modeling; targeted therapy; genome editing; single-cell sequencing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

During the past decade, our knowledge of the genomic and epigenomic landscape of acute leukemia, including both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) has been tremendously improved with the identification of key germline and somatic alterations driving leukemogenesis, refining diagnosis and prognostication and providing novel therapeutic targets. Many of these studies from large cohorts of patients have highlighted the importance of detecting and combining patterns of mutations, complex genomic alterations, and aberrant transcriptional signatures of bulk and single cells to properly diagnose and predict therapeutic response.

The fast progress in genetic discovery has been accompanied by the rapid development of faithful cellular and in vivo models, such as genetically modified mice and xenografts of patient-derived cells in immune deficient mice, that have defined leukemia drivers and importance of cellular origin. 

Recent advances in computational modelling techniques and machine learning offer opportunities to advance diagnosis, prediction of prognosis, and selection of therapy.

This Special Issue will highlight the current state-of-the-art in both ALL and AML and future perspectives for improving the functional genomic landscape of leukemia cells, their cell of origin, modeling by faithful in vitro and animal systems, clinical management and therapeutic targeting.

Dr. Ilaria Iacobucci
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 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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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 leukemia
  • Functional genomics
  • Classification
  • Single cells
  • Germline predisposition
  • Mouse models
  • Genome editing
  • Machine learning
  • Therapeutic targeting

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Published Papers (6 papers)

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Research

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13 pages, 1785 KiB  
Communication
Conjoined Genes as Common Events in Childhood Acute Lymphoblastic Leukemia
by Marco Severgnini, Mariella D’Angiò, Silvia Bungaro, Giovanni Cazzaniga, Ingrid Cifola and Grazia Fazio
Cancers 2022, 14(14), 3523; https://doi.org/10.3390/cancers14143523 - 20 Jul 2022
Cited by 1 | Viewed by 2057
Abstract
Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. For the last three decades, conventional cytogenetic and molecular approaches allowed the identification of genetic abnormalities having prognostic and therapeutic relevance. Although the current cure rate in pediatric B cell acute leukemia is [...] Read more.
Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer. For the last three decades, conventional cytogenetic and molecular approaches allowed the identification of genetic abnormalities having prognostic and therapeutic relevance. Although the current cure rate in pediatric B cell acute leukemia is approximately 90%, it remains one of the leading causes of mortality in childhood. Furthermore, in the contemporary protocols, chemotherapy intensity was raised to the maximal levels of tolerability, and further improvements in the outcome will depend on the characterization and reclassification of the disease, as well as on the development of new targeted drugs. The recent technological advances in genome-wide profiling techniques have allowed the exploration of the molecular heterogeneity of this disease, even though some potentially interesting biomarkers such as conjoined genes have not been deeply investigated yet. In the present study, we performed the transcriptome sequencing (RNA-seq) of 10 pediatric B cell precursor (BCP)-ALL cases with different risk (four standard- and six high-risk patients) enrolled in the Italian AIEOP-BFM ALL2000 protocol, in order to characterize the full spectrum of transcriptional events and to identify novel potential genetic mechanisms sustaining their different early response to therapy. Total RNA was extracted from primary leukemic blasts and RNA-seq was performed by Illumina technology. Bioinformatics analysis focused on fusion transcripts, originated from either inter- or intra-chromosomal structural rearrangements. Starting from a raw list of 9001 candidate events, by employing a custom-made bioinformatics pipeline, we obtained a short list of 245 candidate fusions. Among them, 10 events were compatible with chromosomal translocations. Strikingly, 235/245 events were intra-chromosomal fusions, 229 of which involved two contiguous or overlapping genes, resulting in the so-called conjoined genes (CGs). To explore the specificity of these events in leukemia, we performed an extensive bioinformatics meta-analysis and evaluated the presence of the fusions identified in our 10 BCP-ALL cohort in several other publicly available RNA-seq datasets, including leukemic, solid tumor and normal sample collections. Overall, 14/229 (6.1%) CGs were found to be exclusively expressed in leukemic cases, suggesting an association between CGs and leukemia. Moreover, CGs were found to be common events both in standard- and high-risk BCP-ALL patients and it might be suggestive of a novel potential transcriptional regulation mechanism active in leukemic cells. Full article
(This article belongs to the Special Issue Genomic Alterations of Leukemia)
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22 pages, 10112 KiB  
Article
Copy Number Changes and Allele Distribution Patterns of Chromosome 21 in B Cell Precursor Acute Lymphoblastic Leukemia
by M. Reza Abbasi, Karin Nebral, Sabrina Haslinger, Andrea Inthal, Petra Zeitlhofer, Margit König, Dagmar Schinnerl, Stefan Köhrer, Sabine Strehl, Renate Panzer-Grümayer, Georg Mann, Andishe Attarbaschi and Oskar A. Haas
Cancers 2021, 13(18), 4597; https://doi.org/10.3390/cancers13184597 - 13 Sep 2021
Cited by 6 | Viewed by 2659
Abstract
Chromosome 21 is the most affected chromosome in childhood acute lymphoblastic leukemia. Many of its numerical and structural abnormalities define diagnostically and clinically important subgroups. To obtain an overview about their types and their approximate genetic subgroup-specific incidence and distribution, we performed cytogenetic, [...] Read more.
Chromosome 21 is the most affected chromosome in childhood acute lymphoblastic leukemia. Many of its numerical and structural abnormalities define diagnostically and clinically important subgroups. To obtain an overview about their types and their approximate genetic subgroup-specific incidence and distribution, we performed cytogenetic, FISH and array analyses in a total of 578 ALL patients (including 26 with a constitutional trisomy 21). The latter is the preferred method to assess genome-wide large and fine-scale copy number abnormalities (CNA) together with their corresponding allele distribution patterns. We identified a total of 258 cases (49%) with chromosome 21-associated CNA, a number that is perhaps lower-than-expected because ETV6-RUNX1-positive cases (11%) were significantly underrepresented in this array-analyzed cohort. Our most interesting observations relate to hyperdiploid leukemias with tetra- and pentasomies of chromosome 21 that develop in constitutionally trisomic patients. Utilizing comparative short tandem repeat analyses, we were able to prove that switches in the array-derived allele patterns are in fact meiotic recombination sites, which only become evident in patients with inborn trisomies that result from a meiosis 1 error. The detailed analysis of such cases may eventually provide important clues about the respective maldistribution mechanisms and the operative relevance of chromosome 21-specific regions in hyperdiploid leukemias. Full article
(This article belongs to the Special Issue Genomic Alterations of Leukemia)
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14 pages, 2764 KiB  
Article
A Novel Platform to Test In Vivo Single Gene Dependencies in t(8,21) and t(15,17) AML Confirms Zeb2 as Leukemia Target
by Giulia De Conti, Alicja M. Gruszka, Debora Valli, Andrea Umberto Cammarata, Matteo Righi, Massimiliano Mazza and Pier Giuseppe Pelicci
Cancers 2020, 12(12), 3768; https://doi.org/10.3390/cancers12123768 - 14 Dec 2020
Cited by 3 | Viewed by 2016
Abstract
The increased usage of high-throughput technologies in cancer research, including genetic and drug screens, generates large sets of candidate targets that need to be functionally validated for their roles in tumor development. Thus, reliable and robust in vivo model systems are needed to [...] Read more.
The increased usage of high-throughput technologies in cancer research, including genetic and drug screens, generates large sets of candidate targets that need to be functionally validated for their roles in tumor development. Thus, reliable and robust in vivo model systems are needed to perform reverse genetic experiments. Ideally, these models should allow for a conditional silencing of the target and an unambiguous identification of engineered cancer cells. Here, we present a platform consisting of: (i) t(8;21) and t(15;17) driven acute myeloid leukemia (AML) transgenic mice with constitutive expression of green fluorescent protein (GFP) and inducible expression of Cre recombinase, and (ii) REX, a modified pSico lentiviral vector for inducible shRNA expression and red fluorescent protein (RFP) as a selection marker. In this system, leukemic cells from transgenic mice are transduced with REX, flow sorted, and transplanted into syngeneic hosts. Gene interference is induced in established tumors by tamoxifen treatment. Dual-color cell fluorescence guides the in vivo identification of shRNA interfered AML cells, monitoring engraftment and disease progression. We tested the platform by inducing knockdown of Zeb2, a gene upregulated by AML1-ETO and PML-RARα oncogenes in pre-leukemic hematopoietic stem cell compartment, and observed a significant delay in leukemia onset. This proves the power and utility of the platform and confirms Zeb2 contribution to the pathogenesis of AML. Full article
(This article belongs to the Special Issue Genomic Alterations of Leukemia)
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Review

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18 pages, 1103 KiB  
Review
The Mutational Landscape of Myeloid Leukaemia in Down Syndrome
by Carini Picardi Morais de Castro, Maria Cadefau and Sergi Cuartero
Cancers 2021, 13(16), 4144; https://doi.org/10.3390/cancers13164144 - 18 Aug 2021
Cited by 9 | Viewed by 4245
Abstract
Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to [...] Read more.
Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS. Full article
(This article belongs to the Special Issue Genomic Alterations of Leukemia)
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27 pages, 3317 KiB  
Review
Genetic Alterations in Childhood Acute Lymphoblastic Leukemia: Interactions with Clinical Features and Treatment Response
by Shawn H. R. Lee, Zhenhua Li, Si Ting Tai, Bernice L. Z. Oh and Allen E. J. Yeoh
Cancers 2021, 13(16), 4068; https://doi.org/10.3390/cancers13164068 - 12 Aug 2021
Cited by 17 | Viewed by 3859
Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer among children. This aggressive cancer comprises multiple molecular subtypes, each harboring a distinct constellation of somatic, and to a lesser extent, inherited genetic alterations. With recent advances in genomic analyses such as next-generation sequencing [...] Read more.
Acute lymphoblastic leukemia (ALL) is the most common cancer among children. This aggressive cancer comprises multiple molecular subtypes, each harboring a distinct constellation of somatic, and to a lesser extent, inherited genetic alterations. With recent advances in genomic analyses such as next-generation sequencing techniques, we can now clearly identify >20 different genetic subtypes in ALL. Clinically, identifying these genetic subtypes will better refine risk stratification and determine the optimal intensity of therapy for each patient. Underpinning each genetic subtype are unique clinical and therapeutic characteristics, such as age and presenting white blood cell (WBC) count. More importantly, within each genetic subtype, there is much less variability in treatment response and survival outcomes compared with current risk factors such as National Cancer Institute (NCI) criteria. We review how this new taxonomy of genetic subtypes in childhood ALL interacts with clinical risk factors used widely, i.e., age, presenting WBC, IKZF1del, treatment response, and outcomes. Full article
(This article belongs to the Special Issue Genomic Alterations of Leukemia)
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23 pages, 10076 KiB  
Review
Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure
by Hélène Pasquer, Maëlys Tostain, Nina Kaci, Blandine Roux and Lina Benajiba
Cancers 2021, 13(4), 748; https://doi.org/10.3390/cancers13040748 - 11 Feb 2021
Cited by 10 | Viewed by 4033
Abstract
Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding [...] Read more.
Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding of AML leukemogenesis from the preleukemic state to posttherapy relapse. These advances resulted in direct clinical implications with the definition of molecular prognosis classifications, the development of treatment recommendations based on minimal residual disease (MRD) measurement and the discovery of novel targeted therapies, ultimately improving AML patients’ overall survival. The more recent development of functional genomic studies, pushed by novel molecular biology technologies (short hairpin RNA (shRNA) and CRISPR-Cas9) and bioinformatics tools design on one hand, along with the engineering of humanized physiologically relevant animal models on the other hand, have opened a new genomics era resulting in a greater knowledge of AML physiopathology. Combining descriptive and functional genomics will undoubtedly open the road for an AML cure within the next decades. Full article
(This article belongs to the Special Issue Genomic Alterations of Leukemia)
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