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Blood Mar 2023Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of...
Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of clinical features including nontuberculous mycobacterial, bacterial, fungal, and human papillomavirus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor that gives rise to B lymphocytes, monocytes, natural killer cells, and dendritic cells, leading to cytopenias of these lineages and subsequent infections. The bone marrow failure is typically characterized by hypocellularity. Dysplasia may either be absent or subtle but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelomonocytic leukemia. The latter 3 malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or in STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency, including the following: (1) Why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2? (2) What are the genetic changes that lead to myeloid progression? (3) What causes the apparent genetic anticipation? (4) What is the role of preemptive HSCT?
Topics: Humans; GATA2 Deficiency; Myelodysplastic Syndromes; Myeloproliferative Disorders; Mutation; Germ-Line Mutation; GATA2 Transcription Factor
PubMed: 36455197
DOI: 10.1182/blood.2022017764 -
International Journal of Molecular... May 2021Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red... (Review)
Review
Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies.
Topics: Animals; Erythropoiesis; Homeostasis; Humans; Iron; Iron Overload; Myelodysplastic Syndromes; Reactive Oxygen Species
PubMed: 34068996
DOI: 10.3390/ijms22105202 -
The Medical Clinics of North America Mar 2017Myelodysplastic syndrome (MDS) is a heterogeneous, clonal stem cell disorder of the blood and marrow typically diagnosed based on the presence of persistent... (Review)
Review
Myelodysplastic syndrome (MDS) is a heterogeneous, clonal stem cell disorder of the blood and marrow typically diagnosed based on the presence of persistent cytopenia(s), dysplastic cells, and genetic markers. Common issues that arise in the clinical management include difficulty confirming MDS diagnosis, lack of a standard approach with novel agents in MDS, and few prospective long-term, randomized controlled MDS clinical studies to guide allogeneic blood and marrow transplant. With the recent genetic characterization of MDS, certain aspects of these issues will be better addressed by integrating genetic data into clinical study design and clinical practice.
Topics: Bone Marrow Cells; Chromatin Assembly and Disassembly; DNA Methylation; Hematologic Tests; Humans; Mutation; Myelodysplastic Syndromes; Prognosis; RNA Splicing
PubMed: 28189174
DOI: 10.1016/j.mcna.2016.09.006 -
Medicina (Kaunas, Lithuania) Jul 2020Myelodysplastic syndrome (MDS) is a clonal disease characterized by multilineage dysplasia, peripheral blood cytopenias, and a high risk of transformation to acute... (Review)
Review
Myelodysplastic syndrome (MDS) is a clonal disease characterized by multilineage dysplasia, peripheral blood cytopenias, and a high risk of transformation to acute myeloid leukemia. In theory, from clonal hematopoiesis of indeterminate potential to hematologic malignancies, there is a complex interplay between genetic and epigenetic factors, including miRNA. In practice, karyotype analysis assigns patients to different prognostic groups, and mutations are often associated with a particular disease phenotype. Among myeloproliferative disorders, secondary MDS is a group of special entities with a typical spectrum of genetic mutations and cytogenetic rearrangements resembling those in de novo MDS. This overview analyzes the present prognostic systems of MDS and the most recent efforts in the search for genetic and epigenetic markers for the diagnosis and prognosis of MDS.
Topics: Biomarkers; Core Binding Factor Alpha 2 Subunit; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; DNA-Binding Proteins; Dioxygenases; Humans; Mutation; Myelodysplastic Syndromes; Phosphoproteins; Prognosis; Proto-Oncogene Proteins; RNA Splicing Factors; Repressor Proteins; Serine-Arginine Splicing Factors
PubMed: 32727068
DOI: 10.3390/medicina56080376 -
CMAJ : Canadian Medical Association... Jul 2016
Topics: Aged; Anemia, Macrocytic; Bone Marrow; Erythropoietin; Fatigue; Humans; Lenalidomide; Myelodysplastic Syndromes; Stem Cell Transplantation; Thalidomide
PubMed: 26728842
DOI: 10.1503/cmaj.151077 -
Best Practice & Research. Clinical... Dec 2017A growing number of inherited genetic loci that contribute to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) development in both children as well as adults... (Review)
Review
A growing number of inherited genetic loci that contribute to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) development in both children as well as adults are rapidly being identified. In recognition of the clinical impact of this emerging field, the World Health Organization, National Comprehensive Cancer Network, and European LeukemiaNet have all added consideration of inherited predisposition to MDS/AML classification and management. Study of these disorders is providing unique insight into the biology of both sporadic and familial MDS/AML. International collaborative efforts to store germline tissue, document family histories, and pool data are essential to progress in diagnosing and treating both hereditary and sporadic forms of MDS/AML.
Topics: Genetic Diseases, Inborn; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 29156196
DOI: 10.1016/j.beha.2017.10.002 -
International Journal of Molecular... Jun 2016Myelodysplastic syndrome (MDS) is a spectrum of diseases, characterized by debilitating cytopenias and a propensity of developing acute myeloid leukemia. Comprehensive... (Review)
Review
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.
Topics: Autoimmune Diseases; Autoimmunity; Humans; Immune System; Immunity; Immunomodulation; Immunosuppression Therapy; Immunosuppressive Agents; Myelodysplastic Syndromes
PubMed: 27314337
DOI: 10.3390/ijms17060944 -
International Journal of Hematology Dec 2005
Topics: Antilymphocyte Serum; Cyclosporine; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Myelodysplastic Syndromes; Radiotherapy; Stem Cells
PubMed: 16533744
DOI: 10.1532/IJH97.05139 -
Animal Models and Experimental Medicine Mar 2021Myelodysplastic syndrome (MDS) is a malignant tumor of the hematological system characterized by long-term, progressive refractory hemocytopenia. In addition, the risk... (Review)
Review
Myelodysplastic syndrome (MDS) is a malignant tumor of the hematological system characterized by long-term, progressive refractory hemocytopenia. In addition, the risk of leukemia is high, and once it develops, the course of acute leukemia is short with poor curative effect. Animal models are powerful tools for studying human diseases and are highly effective preclinical platforms. Animal models of MDS can accurately show genetic aberrations and hematopoietic clone phenotypes with similar cellular features (such as impaired differentiation and increased apoptosis), and symptoms can be used to assess existing treatments. Animal models are also helpful for understanding the pathogenesis of MDS and its relationship with acute leukemia, which helps with the identification of candidate genes related to the MDS phenotype. This review summarizes the current status of animal models used to research myelodysplastic syndrome (MDS).
Topics: Animals; Genetic Engineering; Humans; Leukemia, Myeloid, Acute; Mice; Models, Animal; Myelodysplastic Syndromes; Rats; Transplantation, Heterologous; Zebrafish
PubMed: 33738439
DOI: 10.1002/ame2.12144 -
Blood Mar 2019Myelodysplastic syndrome (MDS) is characterized by bone marrow failure and a strong propensity for leukemic evolution. Somatic mutations are critical early drivers of... (Review)
Review
Myelodysplastic syndrome (MDS) is characterized by bone marrow failure and a strong propensity for leukemic evolution. Somatic mutations are critical early drivers of the disorder, but the factors enabling the emergence, selection, and subsequent leukemic evolution of these "leukemia-poised" clones remain incompletely understood. Emerging data point at the mesenchymal niche as a critical contributor to disease initiation and evolution. Disrupted inflammatory signaling from niche cells may facilitate the occurrence of somatic mutations, their selection, and subsequent clonal expansion. This review summarizes the current concepts about "niche-facilitated" bone marrow failure and leukemic evolution, their underlying molecular mechanisms, and clinical implications for future innovative therapeutic targeting of the niche in MDS.
Topics: Disease Progression; Genetic Predisposition to Disease; Hematopoietic Stem Cells; Humans; Inflammation; Leukemia; Mesenchymal Stem Cells; Mutation; Myelodysplastic Syndromes; Signal Transduction; Stem Cell Niche
PubMed: 30670448
DOI: 10.1182/blood-2018-10-844639