Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelodysplastic syndromes (MDS) are a highly heterogenous group of hematopoietic tumors, mainly due to variable clinical features and diverse set of cytogenetic, molecular genetic and epigenetic lesions. The major clinical features of MDS are ineffective hematopoiesis, peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemias, which in turn is most likely determined by specific genetic abnormalities and other presenting hematologic features. The risk of developing MDS is relatively higher in some genetic syndromes such as Fanconi anemia and receipt of chemotherapy and radiation treatment. In recent years a significant progress has occurred and a vast literatures has become available including the spectrum of cytogenetic abnormalities, gene mutations relating to RNA splicing machinery, epigenetic regulation of gene expression and signaling pathways associated with MDS pathogenesis, which have provided opportunities to understand the molecular mechanisms as well as employ targeted therapeutic approaches to treat MDS. The cytogenetic abnormalities detected in MDS varies from a single abnormality to complex karyotype not easily amenable to conventional cytogenetic analysis. In such cases, array based high resolution genomic analysis detected abnormalities, which are diagnostic as well as prognostic. The most common driver gene mutations detected in patients with MDS include RNA splicing (SF3B1,SRSF2,U2F1,ZRSR2), DNA methylation (TET2,DNMT3A,IDH1/IDH2), chromatin modification (ASXL1,EZH2), transcription regulation (RUNX1,BCOR) and DNA repair control p53. A small subset of MDS arise due to deregulation of RAS pathway, mainly due to NRAS/KRAS/NF1 mutations. Identification of these mutations and pathways have provided opportunities for oncologists to target these patients with specific therapies. Several drugs which either target the spliceosome, oncogenic RAS signaling, or hypomethylating agents have been employed to successfully treat MDS patients.
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PMID:Genetic and epigenetic pathways in myelodysplastic syndromes: A brief overview. 2549 50

Recent studies have greatly illuminated the genomic landscape of the myelodysplastic syndromes (MDS), and the pace of discovery is accelerating. The most common mutations found in MDS occur in genes involved in RNA splicing (including SF3B1, SRSF2, U2AF1, and ZRSR2) and epigenetic modification (including TET2, ASXL1, and DNMT3A). The identification of spliceosome mutations in approximately half of all patients with MDS implicates abnormalities of RNA splicing, a pathway not previously known as a target for mutation, in the MDS pathogenesis. Several regulators of signal transduction (NRAS, JAK2) and transcription factors (RUNX1, TP53) are also frequently mutated in MDS. The complex patterns of associations between gene mutations identified have revealed epistatic interactions between spliceosome components and epigenetic modifiers in MDS. The cytogenetic abnormalities found in MDS are characterized by the loss of genetic material, whereas translocations are rare. The cytogenetic deletion maps of MDS (e.g., 5q-, 7q-, 20q-) provide us with circumstantial evidence for the presence of tumor suppressor genes. It is now recognized that haploinsufficiency (a gene dosage effect) resulting from gene deletions or inactivating mutations is an important disease mechanism in MDS. Haploinsufficiency of the ribosomal protein gene RPS14 plays a critical role in the development of anemia in the 5q- syndrome, and haploinsufficiency of CUX1 is important in some patients with MDS and AML with complete or partial loss of chromosome 7. Gene expression profiling has identified key deregulated genes and pathways and new prognostic gene signatures in MDS. Recent advances in the molecular pathogenesis of MDS are leading to new biological, clinical, and therapeutic insights.
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PMID:The molecular pathogenesis of the myelodysplastic syndromes. 2564 50

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. Diagnosis is currently based on the presence of peripheral blood cytopenias, peripheral blood and bone marrow dysplasia/blasts, and clonal cytogenetic abnormalities. With the advent of next generation sequencing, recurrent somatic mutations in genes involved in epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, IDH1/2), RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA damage response (TP53), transcriptional regulation (RUNX1, BCOR, ETV6) and signal transduction (CBL, NRAS, JAK2) have been identified in MDS. Conventional prognostication is by the revised International prognostic scoring system (IPSS-R) with additional adverse prognosis conferred by presence of ASXL1, EZH2, or TP53 mutations. Currently Food and Drug administration (FDA)-approved drugs for the treatment of MDS are not curative and their effect on survival is limited; they include the hypomethylating agents (HMA) azacitidine and decitabine and lenalidomide for MDS with isolated del(5q). To date, allogeneic stem cell transplant (ASCT) remains the only treatment option for possible cure. Given the current lack of drugs with convincing evidence of favorable effect on survival, we consider ASCT as the treatment of choice for most patients with symptomatic disease, and especially for those with high-risk disease. For nontransplant candidates, participation in clinical trials is preferred over conventional therapy. There is not one right way of treatment for patients who are not candidates for either ASCT or clinical trials and palliative drugs of choice depend on the clinical problem, such as symptomatic anemia (ESAs, danazol, HMA), thrombocytopenia (HMA), or neutropenia (myeloid growth factors). Conversely, there is no controlled evidence to support the use of iron chelating agents in MDS. Going forward, we believe it is time to incorporate mutation information in clinically derived prognostic models in MDS and encourage development of novel drugs with disease-modifying activity.
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PMID:Myelodysplastic syndromes: Contemporary review and how we treat. 2676 28

Here we report a case of refractory macrocytic anemia with a spliceosomal point mutation involving the ZRSR2 gene in a child with Down syndrome (DS). Such mutations have been shown to cause refractory macrocytic anemia and myelodysplastic syndrome (MDS) in elderly individuals. We report the hematological indices of a child with DS and a ZRSR2 spliceosomal mutation. DS is known to produce macrocytic anemia but does not lead to transfusion dependence. In this case, the ZRSR2 mutation was the likely implicating factor for severe transfusion-dependent anemia in a child with DS. The clinical implication of a ZRSR2 mutation in a child with DS has not been previously described and warrants close surveillance to detect potential insidious transformation to MDS.
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PMID:ZRSR2 mutation in a child with refractory macrocytic anemia and Down Syndrome. 3136 Nov 76