Critically short telomeres in acute myeloid leukemia with loss or gain of parts of chromosomes

Abstract

Telomeres, nucleoprotein complexes at chromosome ends, protect chromosomes against end-to-end fusion. Previous in vitro studies in human fibroblast models indicated that telomere dysfunction results in chromosome instability. Loss of telomere function can result either from critical shortening of telomeric DNA or from loss of distinct telomere-capping proteins. It is less clear whether telomere dysfunction has an important role in human cancer development in vivo. Acute myeloid leukemia (AML) is a good model to study mechanisms that generate chromosome instability in human cancer development because distinct groups of AML are characterized either by aberrations that theoretically could result from telomere dysfunction (terminal deletions, gains/losses of chromosome parts, nonreciprocal translocations), or aberrations that are unlikely to result from telomere dysfunction (e.g., reciprocal translocations or inversions). Here we demonstrate that AML with multiple chromosome aberrations that theoretically could result from telomere dysfunction is invariably characterized by critically short telomeres. Short telomeres in this group are not associated with low telomerase activity or decreased expression of essential telomeric capping proteins TRF2 and POT1. In contrast, telomerase activity levels are significantly higher in AML with short telomeres. Notably, short telomeres in the presence of high telomerase may relate to significantly higher expression of TRF1, a negative regulator of telomere length. Our observations suggest that, consistent with previous in vitro fibroblast models, age-related critical telomere shortening may have a role in generating chromosome instability in human AML development.

Telomere length and LINE1 methylation is associated with chromosomal aberrations in peripheral blood

“…Shorter telomere length was found to be more related with chromosome-type than chromatidtype aberrations, which is in line with chromosomal aberration patterns observed in tumor cells with short telomeres (Gisselsson et al, 2001;Swiggers et al, 2006), and further, stresses the notion that shorter telomere length may cause chromosomal instability that develop into neoplasia. Opposite to telomere length, higher degree of average LINE1 methylation was more related with chromatid-type than chromosome-type aberrations.…”

“…Short telomere length caused chromosomal instability and epithelial carcinogenesis in mice (Artandi et al, 2000). In humans, correlations between short telomeres and chromosomal aberrations have been observed in solid tumor cells (Gisselsson et al, 2001;Stewenius, 2005) and in patients with different types of leukemia (Hartmann et al, 2005;Swiggers et al, 2006). Taken together, these observations indicate that telomere length might be a susceptibility marker for chromosomal aberrations in peripheral blood in individuals without malignancy.…”

Telomere dysfunction and its role in haematological cancer

“…Despite this shortening, these tumours often show evidence of increased levels of TA (Ohyashiki et al, 1997a;Xu et al, 1998;Engelhardt et al, 2000;Swiggers et al, 2006;Wang et al, 2010;Capraro et al, 2011). If telomere shortening in these leukaemias is primarily driven by end-replication losses, and the presence of telomerase can slow the rate telomere shortening, then the telomere shortening in these tumours may be driven by higher levels of cell division compared to tumours exhibiting similar TLs but lower levels of TA.…”

Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia

“…4 Research in oncogenesis is now focusing on the other telomeric genes, especially the shelterin complex. [5][6][7][8][9][10] Specific changes in the expression of these genes in cancers may provide new knowledge about oncogenesis and useful clinical markers, but would also lead to the development of new therapeutic agents.…”

“…4 Research in oncogenesis is now focusing on the other telomeric genes, especially the shelterin complex. [5][6][7][8][9][10] Specific changes in the expression of these genes in cancers may provide new knowledge about oncogenesis and useful clinical markers, but would also lead to the development of new therapeutic agents.B-cell chronic lymphocytic leukemia (B-CLL) results from the progressive accumulation of a leukemic clone (for review, see Chiorazzi and Ferrarini 11 ) that shows lower telomerase activity at disease onset 12 and increased activity in advanced stages and bad prognosis group. 13 Telomeres are shorter in B-CLL cells versus normal B cells, and especially short for patients with bad prognosis.…”