Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was conducted on 13 patients with Fanconi anemia. 25 parents and 12 siblings. The chromosomal instability characteristic of this congenital breakage syndrome was associated with the presence of transferable clastogenic material in the plasma, as also reported previously for ataxia telangiectasia and Bloom's syndrome. While all plasma ultrafiltrates from homozygotes had chromosome damaging properties, the clastogenic material had to be concentrated in most heterozygotes to reach detectable levels. The clastogenic effect was exerted via the intermediacy of superoxide radicals, since it was regularly inhibited by superoxide dismutase (SOD). This adds further evidence for a prooxidant state in this hereditary disease. The autosustained clastogenic activity possibly plays a role in the progressive impairment of blood cell-producing bone marrow and may predispose patients to develop cancer and leukemia. Prophylactic use of antioxidants may be recommended, using clastogenic plasma activity as a guide.
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PMID:Transferable clastogenic activity in plasma from patients with Fanconi anemia. 760 48

Myelodysplastic syndrome (MDS) in childhood is considered to be very rare, but sound epidemiologic data are lacking. We report a population-based study of MDS in Denmark from 1980 to 1991. The medical charts were reviewed of 988 children identified from the Danish National Hospital Discharge Registry with a diagnosis of myeloid leukemia or blood cytopenia. Blood and bone marrow smears from all cases of possible MDS were re-evaluated. The cases were categorized according to the FAB classification, with the exception of chronic myelomonocytic leukemia (CMML) in which more than 5% myeloblasts in the blood was accepted. Juvenile chronic myeloid leukemia (JCML) was included as CMML. MDS was diagnosed in 46 children representing 9% of all hematologic malignancies in children less than 15 years of age. The annual incidence was 4.0/million and did not increase with time. Refractory anemia with excess of blasts and CMML each accounted for one third of the cases. Down syndrome was present in seven children. Other predisposing conditions included Fanconi anemia, neurofibromatosis, constitutional trisomy 8 mosaicism, and familial leukemia. Only one child had therapy-related MDS. The study indicates that the incidence of childhood MDS is higher than generally assumed and approximate to the incidence of acute myeloid leukemia.
Leukemia 1995 Sep
PMID:Childhood myelodysplastic syndrome in Denmark: incidence and predisposing conditions. 765 25

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.
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PMID:Bone marrow transplantation for Fanconi anemia. 767 Jan 20

Fanconi anemia (FA) is one of a group of disorders characterized at the cellular level by a combination of hypersensitivity to DNA-damaging agents, chromosomal instability, and defective DNA repair. Clinical features of FA include pancytopenia, often accompanied by specific congenital malformations, and a predisposition to leukemia. Since the hematological manifestations are the critical defect in terms of prognosis, FA is a candidate disease for gene replacement therapy, and the development of a mouse model system is essential for the initial stages of this work. Previously, we have cloned the gene defective in FA group C by complementation of the intrinsic sensitivity of FA cells to DNA cross-linking agents. We have now cloned the murine homologue of the human FACC cDNA. The mouse cDNA (Facc) shares 79% amino acid sequence similarity with the human gene product. The expression of the mouse cDNA in human FA(C) cells restores the cellular drug sensitivity to normal levels. Thus, the function of the protein has been conserved despite the significant sequence divergence. PCR analysis of mouse tissue RNA reveals that the gene is expressed in all adult tissues, while in situ RNA hybridization experiments show tissue specific expression at late stages of fetal development. Cross-hybridizing sequences exist in DNA from other mammals, chicken and Drosophila. These results support the hypothesis that the FACC gene product has a role in a basic aspect of cellular protection against DNA damaging agents and that this function has been conserved during evolution.
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PMID:Cloning and analysis of the murine Fanconi anemia group C cDNA. 768 6

Fanconi anemia is a rare, autosomal recessive disorder characterized at the cellular level by a combination of hypersensitivity to DNA-damaging agents and chromosomal instability. Clinical features include pancytopenia, often associated with specific congenital malformations, and a predisposition to leukemia. We previously cloned the gene defective in Fanconi anemia group C by complementation of the intrinsic sensitivity of Fanconi anemia cells to DNA cross-linking agents, and we recently cloned its mouse homolog (Facc). In this report, we localized Facc to mouse Chromosome (Chr) 13 and its rat homolog to rat Chr 17. A previously described anemic mouse mutant, flexed-tail, maps to the same chromosomal region. Differences were detected between DNA of the flexed-tail and congenic mice, indicating the proximity of the Facc probe to the disease mutation. Analysis of flexed-tail RNA did not reveal detectable difference in Facc message level or size between flexed-tail and congenic mice. On this basis, we conclude that, although flexed-tail remains a candidate for Fanconi anemia in the mouse, there is no evidence currently that Facc is mutated in flexed-tail mice.
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PMID:Mapping of the murine and rat Facc genes and assessment of flexed-tail as a candidate mouse homolog of Fanconi anemia group C. 769 Jun 22

Fanconi anaemia (FA) is an autosomal recessive disease featuring diverse clinical symptoms in addition to chromosomal instability and hypersensitivity to crosslinking agents. The much increased risk of FA patients developing leukaemia and squamous cell carcinomas makes FA an important model disease for cancer predisposition. Studies documenting the characteristics of FA cells and their response to environmental toxins have failed thus far to disclose the basic cellular process that is primarily disturbed in FA cells. Complementation analysis suggests that mutations in at least four different genes can cause FA (complementation groups FA-A to FA-D). The cDNA for FA-C has been cloned and found to encode a novel protein that localises to the cytoplasmic compartment of cells. Even though the protein's function is still unknown at present, research has now reached the point from where rapid progress to a detailed understanding of this syndrome may be foreseen.
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PMID:Fanconi anaemia research: current status and prospects. 771 36

Fanconi anemia (FA) is a clinically and genetically heterogenous disease that is usually diagnosed on the basis of chromosomal instability reflecting the hypersensitivity towards the DNA cross-linking agents diepoxybutane (DEB) and/or mitomycin C. A less well-known cellular feature that characterizes FA patients is an intrinsic cell cycle disturbance consisting of prolonged progression through, and arrest within, the G2 phase compartment of the cell cycle. In a collaborative blind study, we have evaluated 72-hour lymphocyte cultures from 66 patients with clinical suspicion of FA both for DEB sensitivity and cell cycle disturbance. A concordant result was obtained in 63 of 66 cases. Each of the 3 discordant, but only 1 of the concordant cases presented with overt leukemia. Seventeen cases were identified as classical FA because of their increased DEB sensitivity and G2 phase blockage. Five cases showed a cell cycle disturbance but only borderline DEB sensitivity. These cases might represent atypical or nonclassical forms of FA. They would have been missed by cell cycle studies without concomitant DEB testing. Used in conjunction, cytogenetic and flow cytometric testing provide for the currently optimal diagnosis of FA in nonleukemic patients.
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PMID:Comparative evaluation of diepoxybutane sensitivity and cell cycle blockage in the diagnosis of Fanconi anemia. 771 95

Acute myelogenous leukemia (AML) is the second most common leukemia in children, with approximately 400 new cases occurring annually in the United States. Worldwide, the highest rates of childhood AML occur in Asia and the lowest rates are reported from India and South America. Numerous genetic risk factors for childhood AML have been defined, including Down syndrome, neurofibromatosis, and Fanconi anemia. Research into environmental risk factors has been limited by the rarity of this disease; however, studies of AML in adults have implicated ionizing radiation, solvents, and petroleum products as potential etiologic agents. The largest analytic study of childhood AML found that occupational exposures of either parent to pesticides, paternal exposure to petroleum products, and postnatal exposures to pesticides are increased in children with AML. In addition, maternal use of marijuana during pregnancy was associated with an increased risk of AML, especially the monocytic subtypes. Further study of childhood AML, including occurrence of the disease as a second malignancy, is needed in order to confirm these findings and to increase our understanding of this leukemia.
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PMID:Epidemiology of childhood acute myelogenous leukemia. 774 71

Although bone marrow transplantation (BMT) can eliminate the hematologic manifestations of Fanconi anemia (FA), patients are unusually susceptible to complications associated with the use of cyclophosphamide (CY) in the conditioning regimen. To investigate modifications of the conditioning regimen, we reviewed the records of 24 patients with FA who received an allogeneic BMT. All patients presented with severe pancytopenia. One patient was transplanted with overt leukemia as well. Donors were HLA-identical siblings in 22 cases and 1- and 2-antigen mismatched relatives in two cases, respectively. All conditioning regimens included CY 200 mg/kg in 10 patients; 140 mg/kg with or without antithymocyte globulin in 12 and 20 mg/kg with 400 cGy total body irradiation in two. GVHD prophylaxis comprised methotrexate and/or cyclosporine. Only one of 21 evaluable patients did not show signs of engraftment. Toxicities included grade III/IV mucositis in 20 patients, severe dermatitis in four and veno-occlusive disease in four. Acute GVHD (> or = grade II) occurred in nine of 22 patients. Four patients developed chronic GVHD. With a median follow-up time of 24 months, 14 of the 24 patients are alive with normal hematopoietic function. Eight of the 10 patients with matched sibling donors who were conditioned with CY 140 mg/kg are alive and well. We conclude that BMT is an effective treatment for FA. Conditioning regimens using lower doses of CY are associated with manageable toxicity and can potentially increase the survival rate of patients with HLA-matched donors.
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PMID:Bone marrow transplantation for patients with Fanconi anemia: a study of 24 cases from a single institution. 777 21

Spontaneous and induced chromosomal breakage is an important cellular feature of Fanconi anemia (FA), an inherited DNA repair disorder characterized by progressive bone marrow failure, developmental abnormalities, and predisposition to leukemia. We have previously reported that in comparison to normal cells, there is a substantial increase in frequency of intragenic deletions at an endogenous locus (HPRT) in FA lymphoblasts. Taken together with the increased chromosomal instability, these observations indicated that the wild-type FA gene(s) plays an important role in the maintenance of the genomic integrity. To obtain information on the mechanism(s) underlying the genomic rearrangements in FA, the breakpoint sites of deletions in 11 FA-derived HPRT- mutants were analyzed. The results indicate that a significant proportion of deletions involving a loss of a given exon are identical and that two deletions of different size have the same 3' breakpoint. Interestingly, it appears that in most of the mutants there is a common deletion signal sequence, which suggests that the mutations in the FA gene(s) may lead to an aberrant site-specific cleavage activity that might be responsible for the deletion proneness and the chromosomal instability characteristic of the FA pathology. From the similarity or even identity of the signal sequence at some of the breakpoints with the consensus heptamer which directs cleavage and joining in the assembly of immunoglobulin and T-cell receptor genes, we speculate that steps in common with the V(D)J recombinational process may be illegitimately involved in FA cells.
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PMID:The molecular mechanism underlying formation of deletions in Fanconi anemia cells may involve a site-specific recombination. 784 61


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