Molecular pathogenesis of Fanconi anemia

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Fanconi anemia (FA) is a genetically heterogeneous inherited disorder characterized by bone marrow failure and congenital anomalies. Although an increasing number of reports suggest that reverse mosaicism noted in peripheral blood lymphocytes (PBL) is associated with mild hematopoietic failure in FA, direct examination of myeloid cells have been done in few cases. We found a patient with prolonged mild pancytopenia in whom proliferation of revertant cells was detected in mature myeloid cells but not in PBL. While this patient had inherited heterozygous mutations, 2546delC and 3720-3724del, in the major Fanconi anemia gene FANCA, lymphoblastoid cells from the patient had 2546C>T instead of 2546delC, resulting in expression of a functional missense protein. Since the identical reversion was detected in polymorphonuclear granulocytes and mononuclear phagocytes, sustained hematopoiesis in the patient is attributed to selective growth advantage of revertant myeloid cells. It is noteworthy t … More hat such a myeloid lineage-selective mosaicism is overlooked in routine examination of PBL. Recognition of this status will expand the role of reverse mosaicism in the pathophysiology of FA. Bone marrow failure in FA often shows progression to myelodysplastic syndrome (MDS) and leukemia, which may be attributed to mutations of oncogenes and tumor suppressor genes based on DNA repair deficiency. However, specific mutations of these genes have not been identified in FA leukemic cells. We hypothesized that epigenetic abnormalities may be associated with the pathophysiology of FA. To address this question, we analyzed promoter methylation of five tumor suppressor genes, p15, p16. DAP kinase, RAR-β, E-cadherin. The results showed that 8 of 11 patients (72.7%) had hypermethylation in one or more of these genes. The methylation abnormalities were observed more frequently in patients with MDS than in those without MDS. These results suggest that epigenetic abnormalities might be involbed in leukmogensis in FA. Less