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Genetics and Genomics of Blood Disorders
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Genetics and Genomics of Blood Disorders

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

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 28106

Special Issue Editors

Dr. Orietta Spinelli

E-Mail Website
Guest Editor
Hematology Division, ASST-Papa Giovanni XXIII Hospital, Piazza OMS, 124127 Bergamo, Italy
Interests: genetics of hematologic diseases; acute leukemias; minimal residual disease (MRD); next generation sequencing (NGS)
Dr. Silvia Salmoiraghi

E-Mail Website
Guest Editor
Hematology Division, ASST-Papa Giovanni XXIII Hospital, Piazza OMS, 124127 Bergamo, Italy
Interests: genetics of hematologic diseases; acute leukemias; CLL; next generation sequencing (NGS)

Special Issue Information

Dear Colleagues, 

Blood disorders comprise a large number of oncologic and non-oncologic diseases affecting all hematologic cell lineages. Some genetic alterations have been known as the cause of these diseases for many decades. Conversely, other specific genetic features have been linked to these diseases only recently.

Technological advances have had a huge impact on the discovery of new genomic features and are useful in defining the sequential acquisition of genetic alteration during disease evolution. Furthermore, the effort to correlate genetic abnormalities and patients’ outcomes is helping us to understand the impact of such alterations on disease evolution.

Many different types of DNA damage, such as translocations, deletions, duplications, and mutations, are known to be causative of pathology when affecting genes coding for proteins involved in basic cell pathways, as well as in specific hematologic functions. Less information is available for such alterations when they occur in regulatory regions of the genome, e.g., in the huge amount of so-called “non-coding DNA”. Much is known; however, much more is yet to be known.

This Special Issue in Genes on “Genetics and Genomics of Blood Disorders” will provide an overview of the known genetic features of different hematologic diseases and recent observation in this expanding field.

Dr. Orietta Spinelli
Dr. Silvia Salmoiraghi
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

  • hematologic disease
  • gene mutations
  • genomic alterations
  • next generation sequencing (NGS)
  • molecular alterations
  • minimal residual disease (MRD)
  • disease evolution

Published Papers (6 papers)

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Research

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13 pages, 3969 KiB  
Article
A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)
by Alessandra Venanzi, Roberta Rossi, Giovanni Martino, Ombretta Annibali, Giuseppe Avvisati, Maria Grazia Mameli, Paolo Sportoletti, Enrico Tiacci, Brunangelo Falini and Maria Paola Martelli
Genes 2021, 12(9), 1426; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091426 - 16 Sep 2021
Cited by 3 | Viewed by 2380
Abstract
Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of [...] Read more.
Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES), at the bases of exportin-1(XPO1)-mediated aberrant cytoplasmic NPM1. Immunohistochemistry (IHC) detects cytoplasmic NPM1 and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti-NPM1 mutant specific antibodies is another approach to identify NPM1-mutated AML. Here, we show that among 382 AML cases with NPM1 exon 12 mutations, one was not recognized by WB, and describe the discovery of a novel combination of two mutations involving exon 12. This appeared as a conventional mutation A with the known TCTG nucleotides insertion/duplication accompanied by a second event (i.e., an 8-nucleotide deletion occurring 15 nucleotides downstream of the TCTG insertion), resulting in a new C-terminal protein sequence. Strikingly, the sequence included a functional NES ensuring cytoplasmic relocation of the new mutant supporting the role of cytoplasmic NPM1 as critical in AML leukemogenesis. Full article
(This article belongs to the Special Issue Genetics and Genomics of Blood Disorders)
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Review

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18 pages, 1518 KiB  
Review
Targeting the CDK6 Dependence of Ph+ Acute Lymphoblastic Leukemia
by Patrizia Porazzi, Marco De Dominici, Joseph Salvino and Bruno Calabretta
Genes 2021, 12(9), 1355; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12091355 - 29 Aug 2021
Cited by 5 | Viewed by 4105
Abstract
Ph+ ALL is a poor-prognosis leukemia subtype driven by the BCR-ABL1 oncogene, either the p190- or the p210-BCR/ABL isoform in a 70:30 ratio. Tyrosine Kinase inhibitors (TKIs) are the drugs of choice in the therapy of Ph+ ALL. In combination with standard chemotherapy, [...] Read more.
Ph+ ALL is a poor-prognosis leukemia subtype driven by the BCR-ABL1 oncogene, either the p190- or the p210-BCR/ABL isoform in a 70:30 ratio. Tyrosine Kinase inhibitors (TKIs) are the drugs of choice in the therapy of Ph+ ALL. In combination with standard chemotherapy, TKIs have markedly improved the outcome of Ph+ ALL, in particular if this treatment is followed by bone marrow transplantation. However, resistance to TKIs develops with high frequency, causing leukemia relapse that results in <5-year overall survival. Thus, new therapies are needed to address relapsed/TKI-resistant Ph+ ALL. We have shown that expression of cell cycle regulatory kinase CDK6, but not of the highly related CDK4 kinase, is required for the proliferation and survival of Ph+ ALL cells. Comparison of leukemia suppression induced by treatment with the clinically-approved dual CDK4/6 inhibitor palbociclib versus CDK6 silencing revealed that the latter treatment was markedly more effective, probably reflecting inhibition of CDK6 kinase-independent effects. Thus, we developed CDK4/6-targeted proteolysis-targeting chimeras (PROTACs) that preferentially degrade CDK6 over CDK4. One compound termed PROTAC YX-2-107, which degrades CDK6 by recruiting the Cereblon ubiquitin ligase, markedly suppressed leukemia burden in mice injected with de novo or TKI-resistant Ph+ ALL. The effect of PROTAC YX-2-107 was comparable or superior to that of palbociclib. The development of CDK6-selective PROTACs represents an effective strategy to exploit the “CDK6 dependence” of Ph+ ALL cells while sparing a high proportion of normal hematopoietic progenitors that depend on both CDK6 and CDK6 for their survival. In combination with other agents, CDK6-selective PROTACs may be valuable components of chemotherapy-free protocols for the therapy of Ph+ ALL and other CDK6-dependent hematological malignancies. Full article
(This article belongs to the Special Issue Genetics and Genomics of Blood Disorders)
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10 pages, 266 KiB  
Review
The Genetics of Myelodysplastic Syndromes: Clinical Relevance
by Chiara Chiereghin, Erica Travaglino, Matteo Zampini, Elena Saba, Claudia Saitta, Elena Riva, Matteo Bersanelli and Matteo Giovanni Della Porta
Genes 2021, 12(8), 1144; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081144 - 27 Jul 2021
Cited by 16 | Viewed by 5202
Abstract
Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic [...] Read more.
Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance. Full article
(This article belongs to the Special Issue Genetics and Genomics of Blood Disorders)
20 pages, 2600 KiB  
Review
T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness
by Valentina Bardelli, Silvia Arniani, Valentina Pierini, Danika Di Giacomo, Tiziana Pierini, Paolo Gorello, Cristina Mecucci and Roberta La Starza
Genes 2021, 12(8), 1118; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12081118 - 23 Jul 2021
Cited by 38 | Viewed by 7349
Abstract
T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease [...] Read more.
T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options. Full article
(This article belongs to the Special Issue Genetics and Genomics of Blood Disorders)
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14 pages, 1161 KiB  
Review
Immune Gene Rearrangements: Unique Signatures for Tracing Physiological Lymphocytes and Leukemic Cells
by Michaela Kotrova, Nikos Darzentas, Christiane Pott, Claudia D. Baldus and Monika Brüggemann
Genes 2021, 12(7), 979; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12070979 - 27 Jun 2021
Cited by 9 | Viewed by 3010
Abstract
The tremendous diversity of the human immune repertoire, fundamental for the defense against highly heterogeneous pathogens, is based on the ingenious mechanism of immune gene rearrangements. Rearranged immune genes encoding the immunoglobulins and T-cell receptors and thus determining each lymphocyte’s antigen specificity are [...] Read more.
The tremendous diversity of the human immune repertoire, fundamental for the defense against highly heterogeneous pathogens, is based on the ingenious mechanism of immune gene rearrangements. Rearranged immune genes encoding the immunoglobulins and T-cell receptors and thus determining each lymphocyte’s antigen specificity are very valuable molecular markers for tracing malignant or physiological lymphocytes. One of their most significant applications is tracking residual leukemic cells in patients with lymphoid malignancies. This so called ‘minimal residual disease’ (MRD) has been shown to be the most important prognostic factor across various leukemia subtypes and has therefore been given enormous attention. Despite the current rapid development of the molecular methods, the classical real-time PCR based approach is still being regarded as the standard method for molecular MRD detection due to the cumbersome standardization of the novel approaches currently in progress within the EuroMRD and EuroClonality NGS Consortia. Each of the molecular methods, however, poses certain benefits and it is therefore expectable that none of the methods for MRD detection will clearly prevail over the others in the near future. Full article
(This article belongs to the Special Issue Genetics and Genomics of Blood Disorders)
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14 pages, 1121 KiB  
Review
Genetic Alterations and Therapeutic Targeting of Philadelphia-Like Acute Lymphoblastic Leukemia
by Ilaria Iacobucci and Kathryn G. Roberts
Genes 2021, 12(5), 687; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050687 - 1 May 2021
Cited by 12 | Viewed by 4824
Abstract
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to BCR-ABL1-positive ALL, Ph-like ALL is characterized [...] Read more.
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to BCR-ABL1-positive ALL, Ph-like ALL is characterized by IKZF1 or other B-lymphoid transcription factor gene deletions and by poor outcome to conventional therapeutic approaches. Genetic alterations are highly heterogenous across patients and include gene fusions, sequence mutations, DNA copy number changes and cryptic rearrangements. These lesions drive constitutively active cytokine receptor and kinase signaling pathways which deregulate ABL1 or JAK signaling and more rarely other kinase-driven pathways. The presence of activated kinase alterations and cytokine receptors has led to the incorporation of targeted therapy to the chemotherapy backbone which has improved treatment outcome for this high-risk subtype. More recently, retrospective studies have shown the efficacy of immunotherapies including both antibody drug-conjugates and chimeric antigen receptor T cell therapy and as they are not dependent on a specific genetic alteration, it is likely their use will increase in prospective clinical trials. This review summarizes the genomic landscape, clinical features, diagnostic assays, and novel therapeutic approaches for patients with Ph-like ALL. Full article
(This article belongs to the Special Issue Genetics and Genomics of Blood Disorders)
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