Abnormality of Telomere Regulation in Bone Marrow Failure Syndrome
Department of Hematology, Nippon Medical School
Dyskeratosis congenita (DKC) is an inherited bone marrow failure syndrome characterized by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome is considered to be a severe form of DKC. Unconventional forms of DKC (cryptic DKC [cDKC]), which develop slowly in adulthood without the physical anomalies characteristic of DKC, have been reported.
The genes responsible for them have been identified as a gene cluster forming a telomerase complex (DKC1, TERC, TERT, NOP10, and NHP2); TINF2, which forms a shelterin complex; TCAB1, which transports the telomerase complex to intranuclear Cajal bodies; and RTEL1, which has a function of the DNA helicase. DKC is thought to occur when a mutation in these genes causes shortening of the telomere, resulting in impaired proliferation in hemopoietic stem cells and other proliferative cells, leading to the symptoms described above.
The pathogenesis of DKC involves 3 important factors: 1) telomere-related gene abnormality leading to intracellular molecular biological mutation, 2) generational anticipation, and 3) aging. The mutations of TERC and TERT seen in cDKC produce a haploinsufficiency effect, but the extent of the weakening of telomerase activity is small, so that a certain level of generational anticipation and aging is thought to be required before the DKC phenotype develops.
Treatment for DKC and cDKC is either by administering anabolic steroid hormones or by allogeneic hemopoietic stem cell transplant. Anabolic steroid hormones are thought to be converted to estrogen in the cell and to enhance telomerase activity through the estrogen-binding region of the TERT promoter region. So far, this treatment has been reported to be effective in approximately two-thirds of cases of DKC, but the proportion of cases in which results can be achieved is unclear. Meanwhile, allogeneic hemopoietic stem cell transplantation (Allo-HSCT) is an effective treatment for serious bone marrow failure in DKC and HHS, but due to posttransplantation lung complications and other issues, the treatment outcomes have been regarded as disappointing. In the future, with the development of conditioning regimens and supportive therapy of Allo-HSCT, this could therefore be a potentially promising therapeutic approach.
日医大医会誌 2015; 11(3), 136-144
dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, shortening of the telomere, telomere-related gene mutation
Hiroki Yamaguchi, Department of Hematology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan