Telomere shortening, TP53 mutations and deletions in chronic lymphocytic leukemia result in increased chromosomal instability and breakpoint clustering in heterochromatic regions

AbstractComplex karyotypes are associated with a poor prognosis in chronic lymphocytic leukemia (CLL). Using mFISH, iFISH, and T/C-FISH, we thoroughly characterized 59 CLL patients regarding parameters known to be involved in chromosomal instability: status of the genesATM andTP53 and telomere length. Interestingly, a deletion of theATM locus in 11q, independent of the cytogenetic context, was associated with significantly diminished risk (p<0.05) of carrying a mutation inTP53. In patients with loss or mutation ofTP53, chromosomal breakage occurred more frequently (p<0.01) in (near-) heterochromatic regions. Median telomere length in patients with complex karyotypes was significantly shorter than that of healthy controls and shorter than in all other cytogenetic cohorts. Furthermore, the median telomere length of patients carrying aTP53 mutation was significantly shorter than without mutation. We conclude that telomere shortening in combination with loss ofTP53 induces increased chromosomal instability with preferential involvement of (near-) heterochromatic regions.
Source: Annals of Hematology - Category: Hematology Source Type: research