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Molecular and Cellular Mechanisms of Myelodysplastic Syndrome

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2016) | Viewed by 60361

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Special Issue Editors

Assoc. Prof. Dr. Vivienne Rebel

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Guest Editor

Greehey Children’s Cancer Research Institute (GCCRI), The University of Texas Health Science Center at San Antonio (UTHSCSA), San Antonio, TX, USA
Interests: myelodysplastic syndrome; hematopoietic stem cells; mouse models; DNA repair

Assoc. Prof. Dr. Sandra Zinkel

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Guest Editor

Department of Medicine, Vanderbilt University School of Medicine, 548 PRB, Nashville, TN 37232, USA
Interests: BCL-2 family; BID; programmed cell death; hematopoiesis; bone marrow failure; DNA damage response; leukemia; apoptosis; biochemistry; cancer; cell cycle; DNA repair; knockout; mass spectroscopy; mouse; phosphorylation; proteomics; signal transduction; stem cells

Special Issue Information

Dear Colleagues,

Myelodysplastic syndrome (MDS) is a group of related, fatal diseases originating in the hematopoietic stem cell (HSC) compartment. It occurs most often in the elderly and in cancer patients after receiving intensive anti-cancer therapy. Since the relative sizes of both of these populations are increasing in many developed countries, MDS is becoming a serious health issue. In fact, based on the Seer database, MDS incidence, at ~75 per 100,000, approaches that of lung cancer. The past 5–10 years of research have led to important discoveries, such as the high prevalence of mutations in known oncogenes and genes encoding components of the RNA processing machinery, as well as the contribution of the HSC microenvironment to the disease development. These recent discoveries shed light on the molecular and cellular mechanisms driving MDS development. The field is now poised to identify better drugs and identify those patients most at risk of developing cancer therapy-related MDS, inspiring hope that improved patient outcomes and personalized chemotherapy to prevent MDS are within reach.

Assoc. Prof. Dr. Vivienne Rebel
Assoc. Prof. Dr. Sandra Zinkel
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.

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Keywords

Disease mechanisms
Hematopoietic stem cells
Bone marrow microenvironment
Animal models
Drug development

Published Papers (6 papers)

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Research

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Open AccessArticle

The Systemic Profile of Soluble Immune Mediators in Patients with Myelodysplastic Syndromes

by Astrid Olsnes Kittang, Kristoffer Sand, Annette Katharina Brenner, Kristin Paulsen Rye and Øystein Bruserud

Int. J. Mol. Sci. 2016, 17(7), 1080; https://doi.org/10.3390/ijms17071080 - 05 Jul 2016

Cited by 14 | Viewed by 4925

Abstract

Introduction: Myelodysplastic syndromes (MDS) are characterized by bone marrow failure due to disturbed bone marrow maturation. MDS is associated with increased risk of transformation to acute myeloid leukemia (AML) and features of immunological dysregulation. Materials and methods: Serum levels of 47 soluble immune mediators were examined in samples derived from 49 MDS patients (35 low-risk and 14 high-risk) and 23 healthy adults. Our patients represent an unselected population-based cohort. The mediators included cytokines, soluble adhesion proteins, matrix metalloproteases, and tissue inhibitors of proteases. Levels were determined using Luminex assays. Patients were classified as low- and high-risk based on the international prognostic scoring system (IPSS) score. Results: When comparing the serum levels of single mediators the MDS patients showed a relatively wide variation range for several mediators compared with healthy adults, especially interleukin 6 (IL-6), IL-8/CXCL8, CCL3, and CCL4. The high-risk patients had lower levels of epidermal growth factor (EGF), cluster of differentiation 40 ligand (CD40L), CCL5, CCL11, CXCL5, matrix metalloproteinase 1 (MMP-1), MMP-9, and tissue inhibitor of metalloproteinases 2 (TIMP-2) compared with low-risk patients. Unsupervised hierarchical cluster analysis visualized marked serum mediator profile differences between MDS patients; based on this analysis three patient subsets could be identified. The healthy adults were also included in this analysis and, as expected, they formed their own separate cluster, except for one outlier. Both low- and high-risk patients showed considerable heterogeneity with regard to serum profile, and this heterogeneity seems stable over time (one year follow-up). Finally, very few mediators differed between low- and high-risk patients, but hierarchical clustering based both on all mediators, as well as five selected mediators (EGF, CCL11, TIMP-2, MMP-1, and MMP-9) identified subsets of patients with significantly increased frequency of high-risk disease (χ-square test p = 0.0158 and p = 0.0148). Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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Review

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Open AccessReview

Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis—Masters of Survival and Clonality?

by Lisa Pleyer, Peter Valent and Richard Greil

Int. J. Mol. Sci. 2016, 17(7), 1009; https://doi.org/10.3390/ijms17071009 - 27 Jun 2016

Cited by 37 | Viewed by 18381

Abstract

Myelodysplastic syndromes (MDS) are malignant hematopoietic stem cell disorders that have the capacity to progress to acute myeloid leukemia (AML). Accumulating evidence suggests that the altered bone marrow (BM) microenvironment in general, and in particular the components of the stem cell niche, including mesenchymal stem cells (MSCs) and their progeny, play a pivotal role in the evolution and propagation of MDS. We here present an overview of the role of MSCs in the pathogenesis of MDS, with emphasis on cellular interactions in the BM microenvironment and related stem cell niche concepts. MSCs have potent immunomodulatory capacities and communicate with diverse immune cells, but also interact with various other cellular components of the microenvironment as well as with normal and leukemic stem and progenitor cells. Moreover, compared to normal MSCs, MSCs in MDS and AML often exhibit altered gene expression profiles, an aberrant phenotype, and abnormal functional properties. These alterations supposedly contribute to the “reprogramming” of the stem cell niche into a disease-permissive microenvironment where an altered immune system, abnormal stem cell niche interactions, and an impaired growth control lead to disease progression. The current article also reviews molecular targets that play a role in such cellular interactions and possibilities to interfere with abnormal stem cell niche interactions by using specific targeted drugs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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Open AccessReview

Immune Mechanisms in Myelodysplastic Syndrome

by Andreas Glenthøj, Andreas Due Ørskov, Jakob Werner Hansen, Sine Reker Hadrup, Casey O’Connell and Kirsten Grønbæk

Int. J. Mol. Sci. 2016, 17(6), 944; https://doi.org/10.3390/ijms17060944 - 15 Jun 2016

Cited by 53 | Viewed by 8669

Abstract

Myelodysplastic syndrome (MDS) is a spectrum of diseases, characterized by debilitating cytopenias and a propensity of developing acute myeloid leukemia. Comprehensive sequencing efforts have revealed a range of mutations characteristic, but not specific, of MDS. Epidemiologically, autoimmune diseases are common in patients with MDS, fueling hypotheses of common etiological mechanisms. Both innate and adaptive immune pathways are overly active in the hematopoietic niche of MDS. Although supportive care, growth factors, and hypomethylating agents are the mainstay of MDS treatment, some patients—especially younger low-risk patients with HLA-DR15 tissue type—demonstrate impressive response rates after immunosuppressive therapy. This is in contrast to higher-risk MDS patients, where several immune activating treatments, such as immune checkpoint inhibitors, are in the pipeline. Thus, the dual role of immune mechanisms in MDS is challenging, and rigorous translational studies are needed to establish the value of immune manipulation as a treatment of MDS. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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Open AccessReview

Hereditary Predispositions to Myelodysplastic Syndrome

by Sarah A. Bannon and Courtney D. DiNardo

Int. J. Mol. Sci. 2016, 17(6), 838; https://doi.org/10.3390/ijms17060838 - 30 May 2016

Cited by 61 | Viewed by 10078

Abstract

Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic disorders characterized by ineffective hematopoiesis, bone marrow dysplasia, and peripheral cytopenias. Familial forms of MDS have traditionally been considered rare, especially in adults; however, the increasing availability of somatic and germline genetic analyses has identified multiple susceptibility loci. Bone marrow failure syndromes have been well-described in the pediatric setting, e.g., Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond–Blackfan anemia (DBA), and Shwachman–Diamond syndrome (SBS), hallmarked by clinically-recognizable phenotypes (e.g., radial ray anomalies in FA) and significantly increased risks for MDS and/or acute myeloid leukemia (AML) in the setting of bone marrow failure. However, additional families with multiple cases of MDS or AML have long been reported in the medical literature with little known regarding potential hereditary etiologies. Over the last decade, genomic investigation of such families has revealed multiple genes conferring inherited risks for MDS and/or AML as the primary malignancy, including RUNX1, ANKRD26, DDX41, ETV6, GATA2, and SRP72. As these syndromes are increasingly appreciated in even apparently de novo presentations of MDS, it is important for hematologists/oncologists to become familiar with these newly-described syndromes. Herein, we provide a review of familial MDS syndromes and practical aspects of management in patients with predisposition syndromes. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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Beyond the Niche: Myelodysplastic Syndrome Topobiology in the Laboratory and in the Clinic

by Eugenia Flores-Figueroa and Dita Gratzinger

Int. J. Mol. Sci. 2016, 17(4), 553; https://doi.org/10.3390/ijms17040553 - 13 Apr 2016

Cited by 10 | Viewed by 7320

Abstract

We review the murine and human microenvironment and hematopoietic stem cell niche in the context of intact bone marrow architecture in man and mouse, both in normal and in myelodysplastic syndrome marrow. We propose that the complexity of the hematopoietic stem cell niche can usefully be approached in the context of its topobiology, and we provide a model that incorporates in vitro and in vivo models as well as in situ findings from intact human marrow to explain the changes seen in myelodysplastic syndrome patients. We highlight the clinical application of the study of the bone marrow microenvironment and its topobiology in myelodysplastic syndromes. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy

by Harinder Gill, Anskar Y. H. Leung and Yok-Lam Kwong

Int. J. Mol. Sci. 2016, 17(4), 440; https://doi.org/10.3390/ijms17040440 - 24 Mar 2016

Cited by 43 | Viewed by 10098

Abstract

Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Myelodysplastic Syndrome)

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