Human bone marrow transplant rejection is associated with telomere cleavage

Telomeres that guard chromosomes are shortened with each cell division beca use of replication-dependent sequence loss at both termini. The gradual ero sion of telomeric length has been directly related to the process of aging in vivo. Recently we have reported, in murine. and human cancer cells treat ed with different apoptogens, cleavage and extrusion of telomeric DNA prior to cell death on one hand and an amplification of telomeric DNA in metasta tic epithelial malignancies of different histopathologic origin on the othe r. This study tested our hypothesis that telomere cleavage is linked to tra nsplant rejection in cancer patients receiving stem cells either from bone marrow (BM) or umbilical cord blood transfusion. Telomere integrity and mit otic catastrophe were studied by cytogenetic and molecular fluorescence in situ hybridization (FISH) techniques in two BM samples taken from a mate st em cell transplant recipient diagnosed with aplastic anemia. The first BM s ample, 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 samp le aspirated 52 days after-transplant gave no metaphases and most interphas e cells appeared dead. FISH preparations of the second BM sample showed cle avage and drastic reduction of telomeric DNA at the time the patient was re jecting the transplant. In contrast, the first BM sample had shown no indic ation of cleavage of the telomeric DNA, although the percentage of telomeri c area was smaller than in the control. The replicative stress imposed on t he stem cells engrafted may result in an accelerated aging effect, possibly due to the erosion of telomeric DNA. We, therefore, conclude that BM rejec tion could be directly associated with the cleavage, clustering, and extrus ion of telomeric DNA in the donor cells.