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)

Specific chromosomal deletions are commonly found in bone marrow cells of children with Fanconi anemia (FA) whose disease has evolved to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Identical deletions are found in adults with MDS/AML with a history of exposure to alkylating agents (secondary MDS/AML). While deleted chromosomal regions likely harbor genes encoding proteins with tumor suppressor (TS) function, such genes have not been identified and the environmental forces by which these mutant clones are selected remain unclear. A consistent signaling abnormality in cells bearing mutations of the Fanconi anemia complementation group C (FA-C) gene (FANCC) has revealed a potential selective force. Hematopoietic progenitor cells from patients and mice with FANCC mutations are hypersensitive to the inhibitory effects of IFNgamma and TNFalpha. Consequently, clonal outgrowths in FA likely result from strong selective pressure for stem and/or progenitor cells resistant to these inhibitory cytokines. Additional mutations that inactivate signaling pathways for these inhibitors would create a cell with a profound proliferative advantage over its apoptosis-prone counterparts. Here, we present preliminary evidence supporting a selection-based model of leukemic evolution and argue that MDS in FA patients is a de facto model of secondary MDS in non-FA adults.
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PMID:Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: a view from the window of Fanconi anemia. 1055 53

Fanconi anemia is a rare autosomal recessive disease characterized by bone marrow failure, developmental anomalies, a high incidence of myelodysplasia and acute nonlymphocytic leukemia, and cellular hypersensitivity to cross linking agents. Five of the seven known Fanconi anemia proteins bind together in a complex and influence the function of a sixth, FANCD2, which colocalizes with BRCA1 in nuclear foci after genotoxic stress. Carboxy-terminal truncating mutations of the seventh Fanconi anemia gene, BRCA2, are hypomorphic and lead to FA-D1 and possibly FA-B. Because the Fanconi anemia alleles of BRCA2 fail to bind to Rad51 in response to genotoxic stress and Rad51 therefore fails to localize to nuclear damage foci, many investigators in the field suspect that the Fanconi anemia pathway supports the integrity of the Rad51 and BRCA1 and BRCA2 pathways as they function in homologous recombination repair. Because these abnormalities are common to all somatic cells, it is unlikely that dysfunction of this particular pathway results in tissue-specific apoptosis of hematopoietic cells. Indeed, at least one of the Fanconi anemia proteins, FANCC, exhibits functions in hematopoietic cells in addition to its role in the complex. Because FANCC protects hematopoietic cells from apoptotic cues in ways that do not require an intact heteromeric Fanconi anemia complex, it is reasonable to expect that the other Fanconi anemia gene products will have independent cytoplasmic and nuclear functions, particularly in hematopoietic and germ cells that seem to rely so substantially on an intact portfolio of Fanconi anemia proteins.
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PMID:Genetic basis of Fanconi anemia. 1248 14

Fanconi anemia (FA) is the most frequent inherited cause of BM failure (BMF). Fifteen FANC genes have been identified to date, the most prevalent being FANCA, FANCC, FANCG, and FANCD2. In addition to classical presentations with progressive BMF during childhood and a positive chromosome breakage test in the blood, atypical clinical and/or biological situations can be seen in which a FA diagnosis has to be confirmed or eliminated. For this, a range of biological tools have been developed, including analysis of skin fibroblasts. FA patients experience a strong selective pressure in the BM that predisposes to clonal evolution and to the emergence in their teens or young adulthood of myelodysplasia syndrome (MDS) and/or acute myeloid leukemia (AML) with a specific pattern of somatic chromosomal lesions. The cellular mechanisms underlying (1) the hematopoietic defect which leads to progressive BMF and (2) somatic clonal evolutions in this background, are still largely elusive. Elucidation of these mechanisms at the molecular and cellular levels should be useful to understand the physiopathology of the disease and to adapt the follow-up and treatment of FA patients. This may also ultimately benefit older, non-FA patients with aplastic anemia, MDS/AML for whom FA represents a model genetic condition.
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PMID:Fanconi anemia. 2216 80