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Kidney360 Oct 2022
Topics: Humans; Kidney; Acute Kidney Injury; Myelodysplastic Syndromes
PubMed: 36514731
DOI: 10.34067/KID.0003102022 -
Current Oncology (Toronto, Ont.) Apr 2024Myelodysplastic neoplasms (MDS) are a heterogenous clonal disorder of hemopoietic stem cells characterized by cytomorphologic dysplasia, ineffective hematopoiesis,... (Review)
Review
Myelodysplastic neoplasms (MDS) are a heterogenous clonal disorder of hemopoietic stem cells characterized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of progression to acute myeloid leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently, prognostication and treatment have been determined by cytogenetic and molecular data. Specific genetic abnormalities, such as deletion of the long arm of chromosome 5 (del(5q)), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcome, as reflected in the recently updated fifth edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and the International Consensus Classification 2022 (ICC 2022) classification systems. Treatment of lower-risk MDS is primarily symptom directed to ameliorate cytopenias. Higher-risk disease warrants disease-directed therapy at diagnosis; however, the only possible cure is an allogenic bone marrow transplant. Novel treatments aimed at rational molecular and cellular pathway targets have yielded a number of candidate drugs over recent years; however few new approvals have been granted. With ongoing research, we hope to increasingly offer our MDS patients tailored therapeutic approaches, ultimately decreasing morbidity and mortality.
Topics: Humans; Myelodysplastic Syndromes
PubMed: 38668051
DOI: 10.3390/curroncol31040148 -
Biology of Blood and Marrow... Jan 2010
Review
Topics: Animals; Antineoplastic Agents, Alkylating; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Humans; Myelodysplastic Syndromes; Radiotherapy
PubMed: 19857585
DOI: 10.1016/j.bbmt.2009.10.019 -
Journal of Clinical Oncology : Official... Mar 2017Myelodysplastic syndrome (MDS) is clonal disorder characterized by ineffective hematopoiesis and a tendency to evolve into acute myeloid leukemia (AML). Genetic studies... (Review)
Review
Myelodysplastic syndrome (MDS) is clonal disorder characterized by ineffective hematopoiesis and a tendency to evolve into acute myeloid leukemia (AML). Genetic studies have enabled the identification of a set of recurrently mutated genes central to the pathogenesis of MDS, which can be organized into a limited number of cellular processes, including RNA splicing, epigenetic and traditional transcriptional regulation, and signal transduction. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis to frank MDS, and, ultimately, to secondary AML. This detailed understanding of the molecular landscape of MDS, coupled with the emergence of cost- and time-effective methodologies for DNA sequencing has led to the introduction of genetic studies into the clinical realm. Here, we review recent advances in our genetic understanding of MDS, with a particular focus on the emerging role for mutational data in clinical management as a potential tool to assist in diagnosis, risk stratification, and therapeutic decision-making.
Topics: Humans; Mutation; Myelodysplastic Syndromes
PubMed: 28297619
DOI: 10.1200/JCO.2016.71.0806 -
Leukemia Dec 2019Overlapping spectrum of mutated genes affected in myelodysplastic syndrome (MDS) and primary acute myeloid leukemia suggest common pathogenic mechanisms. However, the... (Review)
Review
Overlapping spectrum of mutated genes affected in myelodysplastic syndrome (MDS) and primary acute myeloid leukemia suggest common pathogenic mechanisms. However, the frequencies of specific mutations are significantly different between them, which implies they might determine specific disease phenotype. For instance, there are overrepresentations of mutations in RNA splicing factors or epigenetic regulators in MDS. We provide an overview of recent advances in our understanding of the biology of MDS and related disorders. Our focus is how mutations of in splicing factors or epigenetic regulators identified in MDS patients demonstrate phenotypes in knockin/knockout mouse models. For instance, mutant Srsf2 mice could alter Srsf2's normal sequence-specific RNA binding activity. It exhibited changing in the recognition of specific exonic splicing enhancer motifs to drive recurrent missplicing of Ezh2, which reduces Ezh2 expression by promoting nonsense-mediated decay. Consistent with this, SRSF2 mutations are mutually exclusive with EZH2 loss-of-function mutations in MDS patients. We also review how gene editing technology identified unique associations between pathogenic mechanisms and targeted therapy using lenalidomide, including: (i) how haploinsufficiency of the genes located in the commonly deleted region in del(5q) MDS patients promotes MDS; (ii) how lenalidomide causes selective elimination of del(5q) MDS cells; and (iii) why del(5q) MDS patients become resistant to lenalidomide. Thus, this review describes our current understanding of the mechanistic and biological effects of mutations in spliceosome and epigenetic regulators by comparing wild-type normal to mutant function as well as a brief overview of the recent progresses in MDS biology.
Topics: Alleles; Biomarkers; Chromosome Aberrations; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Histones; Humans; Molecular Targeted Therapy; Mutation; Myelodysplastic Syndromes; Phenotype; RNA Splicing
PubMed: 31673113
DOI: 10.1038/s41375-019-0617-3 -
International Journal of Molecular... May 2021Myeloid malignancy is a broad term encapsulating myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Initial studies... (Review)
Review
Myeloid malignancy is a broad term encapsulating myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Initial studies into genomic profiles of these diseases have shown 2000 somatic mutations prevalent across the spectrum of myeloid blood disorders. Epigenetic mutations are emerging as critical components of disease progression, with mutations in genes controlling chromatin regulation and methylation/acetylation status. Genes such as DNA methyltransferase 3A (), ten eleven translocation methylcytosine dioxygenase 2 (), additional sex combs-like 1 (), enhancer of zeste homolog 2 () and isocitrate dehydrogenase 1/2 () show functional impact in disease pathogenesis. In this review we discuss how current knowledge relating to disease progression, mutational profile and therapeutic potential is progressing and increasing understanding of myeloid malignancies.
Topics: Animals; Biomarkers; DNA Methylation; DNA Methyltransferase 3A; Disease Management; Disease Susceptibility; Epigenesis, Genetic; Epigenomics; Gene Expression Profiling; Gene Expression Regulation; Histones; Humans; Molecular Targeted Therapy; Myelodysplastic Syndromes; Myeloproliferative Disorders
PubMed: 34065087
DOI: 10.3390/ijms22095013 -
Annals of the New York Academy of... Mar 2014The familial myelodysplastic (MDS)/acute leukemia (AL) predisposition syndromes are inherited disorders that lead to significantly increased lifetime risks of MDS and AL... (Review)
Review
The familial myelodysplastic (MDS)/acute leukemia (AL) predisposition syndromes are inherited disorders that lead to significantly increased lifetime risks of MDS and AL development. At present, four recognized syndromes have Clinical Laboratory Improvement Amendments--certified testing for their respective germ-line mutations: telomere biology disorders due to mutation of TERC or TERT, familial acute myeloid leukemia (AML) with mutated CEBPA, familial MDS/AML with mutated GATA2, and familial platelet disorder with propensity to myeloid malignancy. These disorders are heterogeneous with regard to their causative genetic mutations, clinical presentation, and progression to MDS/AL. However, as a group, they all share the unique requirement for a high index of clinical suspicion to allow appropriate genetic counseling, genetic testing, and mutation-specific clinical management. In addition, translational investigations of individuals and families with these syndromes provide a rare opportunity to understand key pathways underlying susceptibility and progression to MDS/AL and allow the possibility of novel strategies for the prevention and treatment of both familial and sporadic forms of MDS/AL.
Topics: Genetic Predisposition to Disease; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Translational Research, Biomedical
PubMed: 24467820
DOI: 10.1111/nyas.12346 -
Hematology. American Society of... Dec 2016Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Broad application is hindered by high risks of... (Review)
Review
Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative therapy for myelodysplastic syndrome (MDS). Broad application is hindered by high risks of transplant-related morbidity and mortality, especially in the older age range represented by the MDS population. However, recent advances in strategies to minimize regimen-related toxicity make HCT a viable option for many more patients. Appropriate selection of patients involves consideration of patient factors, including use of geriatric assessment tools and comorbidity scales, that predict risks of regimen-related toxicity as well as disease factors, including genetic markers, which predict survival with both non-HCT and HCT therapy. Optimal timing of HCT for fit patients must consider MDS risk scores and life-years to be gained, with earlier transplantation indicated for patients with intermediate-2 and high-risk disease but judicious delay for lower risk patients. Selection of suitable conditioning regimens must balance risks of toxicity with opportunity for maximum disease control.
Topics: Allografts; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Risk Factors; Transplantation Conditioning
PubMed: 27913519
DOI: 10.1182/asheducation-2016.1.478 -
Stem Cell Research & Therapy Mar 2020Myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematopoietic disorders, which is characterized by cytopenias in the peripheral blood and bone... (Review)
Review
Myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematopoietic disorders, which is characterized by cytopenias in the peripheral blood and bone marrow dysplasia due to ineffective hematopoiesis. Patients with MDS have an increased risk of transformation to acute myeloid leukemia (AML). Although the molecular basis of MDS is heterogeneous, several studies demonstrated the significant contribution of the dysregulated immune system in accelerating MDS progression. The immunosuppressive tumor microenvironment is shown to induce tolerance of MDS blasts, which may result in a further accumulation of genetic aberrations and lead to the disease progression. Increasing evidence shows an expansion of myeloid-derived suppressor cells (MDSCs), a population of inflammation-associated immature cells, in patients with MDS. Interestingly, the increased MDSC populations are shown to be correlated with a risk of disease progression in MDS. In addition, MDS is highly prevalent in aged individuals with non-hematology co-morbidities who are fragile for chemotherapy. Increasing research effort is devoting to identify novel agents to specific targeting of the MDSC population for MDS treatment.
Topics: Aged; Hematopoiesis; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Myeloid-Derived Suppressor Cells; Tumor Microenvironment
PubMed: 32197634
DOI: 10.1186/s13287-020-01647-1 -
Journal of Investigative Medicine High... 2021In this article, we describe a case of neutrophilic dermatosis of the dorsal hands (NDDH) complicated with myelodysplastic syndrome and chronic active hepatitis C...
In this article, we describe a case of neutrophilic dermatosis of the dorsal hands (NDDH) complicated with myelodysplastic syndrome and chronic active hepatitis C infection. NDDH was first suggested by Galaria et al in 2000. After comparing features of NDDH with Sweet syndrome in terms of encompassing clinical, laboratory, and histological characteristics, it can be concluded that "distributional or localized variant" of Sweet syndrome is classified as NDDH. Early diagnosis and treatment can improve prognosis. Systemic glucocorticoids are the mainstay of treatment.
Topics: Glucocorticoids; Hand Dermatoses; Hepatitis C, Chronic; Humans; Myelodysplastic Syndromes; Sweet Syndrome
PubMed: 34334014
DOI: 10.1177/23247096211037458