Bone marrow failure and the telomeropathies

Abstract

Our understanding of the pathophysiology of aplastic anemia is undergoing significant revision, with implications for diagnosis and treatment. Constitutional and acquired disease is poorly delineated, as lesions in some genetic pathways cause stereotypical childhood syndromes and also act as risk factors for clinical manifestations in adult life. Telomere diseases are a prominent example of this relationship. Accelerated telomere attrition is the result of mutations in telomere repair genes and genes encoding components of the shelterin complex and related proteins. Genotype-phenotype correlations show genes responsible for X-linked (DKC1) and severe recessive childhood dyskeratosis congenita, typically with associated mucocutaneous features, and others (TERC and TERT) for more subtle presentation as telomeropathy in adults, in which multiorgan failure may be prominent. Telomerase mutations also are etiologic in familial pulmonary fibrosis and cryptic liver disease. Detection of a telomere disease requires awareness in the clinic, appropriate laboratory testing of telomere content, and genetic sequencing. In treatment decisions, genetic screening of related donors for hematopoietic stem cell transplantation is critical, and androgen therapy may be helpful. Telomeres shorten normally with aging, as well as under environmental circumstances, with regenerative stress and oxidative damage. Telomere biology is complexly related to oncogenesis: telomere attrition is protective by enforcing senescence or apoptosis in cells with a long mitotic history, but telomere loss also can destabilize the genome by chromosome rearrangement and aneuploidy.

Figure 1

Mechanisms of telomere attrition. (A) Physiological telomere attrition in normal individual hematopoietic cells is the result of balance between telomerase mediated telomere elongation and telomere loss with each cell division. Gradual decrease in mean telomere content occurs with age. (B) Germ-line mutations in a telomere repair gene lead to a reduced stem cell pool and severe telomere loss during replication. (C) Regenerative replicative stress during bone marrow failure, recovery after chemotherapy, or hematopoietic transplant also leads to telomere loss due to increased mitotic activity in stem cells and/or progenitors. (D) Reactive oxygen species (generated from radiation, toxins, and inflammation) cause DNA damage and telomere loss as a direct effect on the telomere. HSC, hematopoietic stem cell.

Figure 2

Components of telomere maintenance implicated in human disease. Telomeres are composed of thousands of TTAGGG repeats localized at the ends of linear chromosomes. Telomeres are coated by shelterin, a 6-protein complex (TRF1, TRF2, TIN2, POT1, TPP1, and RAP1) with multiple roles in maintaining telomere length homeostasis by forming the T loops, preventing DNA damage response activation, and recruiting the telomerase complex and modulating its activity. The 3′ end of the telomeric leading strand terminates as a single-stranded overhang, which folds back and invades the double-stranded telomeric helix, forming the T loop. Unwinding of the T loop, needed for telomere elongation, is done by a DNA helicase, RTEL1. Telomerase, the enzyme responsible for telomere elongation, has a 4-protein scaffold (dyskerin, NOP10, NHP2, and GAR) and an RNA template (TERC) and reverse transcriptase TERT. TCAB1 ensures trafficking of the telomerase complex to the telomeric ends. The CST complex has multiple proposed roles through its 3 members (CTC1, STN1, and TEN1); CTC1 inhibits telomerase activity and also promotes lagging strand synthesis by binding single stranded DNA and interacting with α polymerase primase. Components in gray have not been implicated in human disease.

Figure 3

Diagnostic algorithm for germline telomere diseases. Mean telomere content should be done in all patients with suspected bone marrow failure from peripheral blood after Fanconi anemia was ruled out in patients under the age of 40 years. Mean telomere content normalized to age-matched controls can be suggestive of telomere disease if below the first percentile or if associated with a strong family history, warranting genetic testing for inherited mutations in telomere maintenance genes. Leukocytes’ telomere content should be interpreted with caution in patients with leukemia (blasts have short telomeres), MDS, and in individuals who have received chemotherapy. If flow-FISH testing is used, the lymphocyte subsets are more accurate than granulocytes. BMF, bone marrow failure; BMT, bone marrow transplant; DEB, deopxybutane; MMC, mitomycin C; PB, peripheral blood.