Telomerase Gene Mutations, In Northern China Bone Marrow Failure Syndromes And Telomere Length Changes

BackgroundBone marrow failure syndrome is a group of diseases including Aplastic anemia, Melodysplastic syndrome, and paraoxymal nocturnal hemoglobinuria. Some patients with the above mentioned diseases have short telomeres in their peripheral nucleated cells. The length of telomere is maintained by a group of enzymes called telomerase complex. The core components of this complex are a RNA template and a reverse transcriptase, called TERC and TERT, respectively. Recently several studies in the west and Japan have disclosed the presence of telomerase complex gene mutation in a small group of patients with acquired bone marrow failure. They speculated that this small group of patients might represent a subset of cryptogenic DKC, in which the premature exhaustion of hematopoietic reservoir is caused by mutations in the telomerase gene. This group of patients, though very small in number, would benefit from early bone marrow transplantation instead of traditional immunosuppressive therapy. The incidence of aplastic anemia in Asian people is relatively high compared with that in the western country. But there has so far been no study in China about the incidence of telomerase gene mutation in acquired bone marrow failure and about its relationship with telomere length. We therefore collected blood samples from patients with aplastic anemia, MDS, and PNH in northern China and perform mutation analysis in this group of patients. Telomere length is measured by Southern blotting and flow cytometry. It's shortening and the difference between white cell subgroups is evaluated.ObjectivesTo study the incidence of telomerase gene mutation, namely TERC and TERT, in Chinese patients with acquired bone marrow failure and explore its relationship with telomere shortening. To measure telomere length by both Southern blotting and flow-cytometry, and explore the difference of telomere length in white cell subgroups of bone marrow failure patients. ResultsTwo TERC mutations and two TERT mutations were identified in 90 patients. The incidence of telomerase gene mutation in Chinese people with acquired bone marrow failure is 3.4%, similar to that of the western people. The small group of patients carrying TERC and TERT mutations have very short telomeres, compared both with normal controls and with their aplastic counterparts. They represent a group of cryptic congenital bone marrow failure patients and would benefit from early transplantation instead of traditional therapy. It is thus clinically important to screen for this small group of patients. Southern blot showed that some patients with bone marrow failure but without mutation also have short telomeres. The length of their telomere overlaps with that of some patients with MDS-RAEB and acute myelogenous leukemia. Flow cytometry showed similar results and allowed us to measure telomere length in different white cell subgroups, which showed different degree of telomere shortening between mononucleated cells and granulocytes.ConclusionsThe incidence of telomerase gene mutation in Chinese people with acquired bonemarrow failure is 3.4%, similar to that of the western people.This small group of patients has very short telomeres, compared both with normalcontrols and with their aplastic counterparts.Both Southern blot and flow cytometry showed decreased telomere length in somepatients with bone marrow failure but without telomerase mutation. The degree oftelomere shortening is different between momonucleated cells and granulocytes.