Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 68 year old woman was hospitalized because of cervical lymphadenopathy. Hematological data on admission showed anemia, leukopenia with a normal platelet count. Serum serological studies revealed polyclonal hypergammaglobulinemia, a positive microsome and thyroid test, and positive reaction to antithyroglobulin antibody. Microscopic examination of a cervical lymph node revealed malignant lymphoma, diffuse large cells of B cell phenotype. The bone marrow smears revealed hypercellularity with dysplastic features including pseudo-Pelger and other nuclear abnormalities of neutrophils, micromegakaryocytes, dyserythropoiesis with megalobastic changes, 60% ring sideroblast and with no increase in proportion of blast cells (3.6%). A diagnosis of myelodysplastic syndrome (MDS, refractory anemia with ring sideroblast (RARS)) was made. Remission of ML obtained with radiation and subsequent systemic chemotherapy with CHOP-Bleo regimen, although she died 2.5 yr after the diagnosis due to relapse of ML without leukemic transformation of MDS. Although basic disturbances in these three conditions are not clear, it is evident that treatment was not concerned with the pathogenesis in this case, because the three conditions existed without treatment. It may be hypothesized that an initial event which selects a clone of stem cells that retains the capacity to differentiate into myeloid and lymphoid line would manifest with the features of RARS in the myeloid line and with the sort of immunological abnormalities reported in this case. Subsequent events select subclones and these progressively lose terminal differentiation, culminating as B-cell lymphoma.
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PMID:[Malignant lymphoma complicating myelodysplastic syndrome with autoantibody for the thyroid gland]. 926 63

The newly identified protein BLAP75/RMI1 associates with the helicase BLM and is critical for the function of the homologous recombination complex. Mutations altering BLM function are associated with highly elevated cancer susceptibility (Bloom's syndrome). We have analyzed the common polymorphism Ser455Asn in RMI1 and its association with cancer risk in acute myeloid leukemia (AML, N=93), myelodysplatic syndromes (MDS, N=74), and malignant melanoma (MM, N=166). Two control groups were used: one population-based (N=119) and one recruited from spouses of cancer patients (N=189). The results showed a consistent pattern, where carriers of the Asn variant had a significantly increased risk of AML/MDS. The risk of AML/MDS for SerAsn+AsnAsn subjects was odds ratio (OR)=1.7, 95% confidence interval (CI) 1.1-2.5 or MM was OR=1.5, 95% CI 1.0-2.2. Age might modify the effect of RMI1 on cancer risk. This was most evident for MM: AsnAsn homozygotes > or =64 years showed OR=2.7, 95% CI 1.1-6.0, whereas individuals <64 years showed OR=0.87, 95% CI 0.31-2.5. These results indicate a role of low-penetrance genes involved in BLM-associated homologous recombination for cancer risk.
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PMID:Genetic variant of the human homologous recombination-associated gene RMI1 (S455N) impacts the risk of AML/MDS and malignant melanoma. 1790 Aug

Inactivation of the DNA mismatch repair pathway manifests as microsatellite instability, an accumulation of mutations that drives carcinogenesis. Here, we determined whether microsatellite instability in acute myeloid leukemia and myelodysplastic syndrome correlated with chromosomal instability and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity through disruption of DNA repair function. Acute myeloid leukemia cell lines (n=12) and primary cell samples (n=18), and bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients (n=63) were profiled for microsatellite instability using fluorescent fragment polymerase chain reaction. PARP inhibitor sensitivity was performed using cell survival, annexin V staining and cell cycle analysis. Homologous recombination was studied using immunocytochemical analysis. SNP karyotyping was used to study chromosomal instability. RNA silencing, Western blotting and gene expression analysis was used to study the functional consequences of mutations. Acute myeloid leukemia cell lines (4 of 12, 33%) and primary samples (2 of 18, 11%) exhibited microsatellite instability with mono-allelic mutations in CtIP and MRE11. These changes were associated with reduced expression of mismatch repair pathway components, MSH2, MSH6 and MLH1. Both microsatellite instability positive primary acute myeloid leukemia samples and cell lines demonstrated a downregulation of homologous recombination DNA repair conferring marked sensitivity to PARP inhibitors. Similarly, bone marrow mononuclear cells from 11 of 56 (20%) patients with de novo high-risk myelodysplastic syndrome exhibited microsatellite instability. Significantly, all 11 patients with microsatellite instability had cytogenetic abnormalities with 4 of them (36%) possessing a mono-allelic microsatellite mutation in CtIP. Furthermore, 50% reduction in CtIP expression by RNA silencing also down-regulated homologous recombination DNA repair responses conferring PARP inhibitor sensitivity, whilst CtIP differentially regulated the expression of homologous recombination modulating RecQ helicases, WRN and BLM. In conclusion, microsatellite instability dependent mutations in DNA repair genes, CtIP and MRE11 are detected in myeloid malignancies conferring hypersensitivity to PARP inhibitors. Microsatellite instability is significantly correlated with chromosomal instability in myeloid malignancies.
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PMID:Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies. 2334 4

Bloom syndrome is a rare autosomal recessive disease, in which BLM gene is mutated, leading to genome instability and proneness to malignancy. It is characterized by short stature, sun-sensitive rash and immunodeficiency. We present a case of bloom syndrome with myelodysplasia complicated by acute myeloid leukaemia. This case has new ophthalmologic manifestations. We confirmed the diagnosis by detection of high rate of sister chromatid exchange. The patient received chemotherapy but did not tolerate it well and developed fungal pneumonia.
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PMID:Bloom syndrome with myelodysplastic syndrome that was converted into acute myeloid leukaemia, with new ophthalmologic manifestations: the first report from Syria. 3041 Jul 76