Human bone marrow transplant rejection is associated with telomere cleavage

Telomeres that guard chromosomes are shortened with each cell division because of replication-dependent sequence loss at both termini. The gradual erosion of telomeric length has been directly related to the process of aging in vivo. Recently we have reported, in murine and human cancer cells treated with different apoptogens, cleavage and extrusion of telomeric DNA prior to cell death on one hand and an amplification of telomeric DNA in metastatic epithelial malignancies of different histopathologic origin on the other. This study tested our hypothesis that telomere cleavage is linked to transplant rejection in cancer patients receiving stem cells either from bone marrow (BM) or umbilical cord blood transfusion. Telomere integrity and mitotic catastrophe were studied by cytogenetic and molecular fluorescence in situ hybridization (FISH) techniques in two BM samples taken from a male stem cell transplant recipient diagnosed with aplastic anemia. The first BM sample, which was aspirated 27 days after transplant, was mitotically active. Only one of 50 metaphases showed a chromatid break. Every cell karyotyped was of male origin with 46, XY chromosome constitution. The second BM sample aspirated 52 days after transplant gave no metaphases and most interphase cells appeared dead. FISH preparations of the second BM sample showed cleavage and drastic reduction of telomeric DNA at the time the patient was rejecting the transplant. In contrast, the first BM sample had shown no indication of cleavage of the telomeric DNA, although the percentage of telomeric area was smaller than in the control. The replicative stress imposed on the stem cells engrafted may result in an accelerated aging effect, possibly due to the erosion of telomeric DNA. We, therefore, conclude that BM rejection could be directly associated with the cleavage, clustering, and extrusion of telomeric DNA in the donor cells.