POT1 Shelterin Complex Mutations Promote Genomic Instability in CLL

Genomic sequencing studies of chronic lymphocytic leukemia (CLL) samples have characterized mutations in several putative driver genes, including splicing factor 3b, subunit 1 (SF3B1) and NOTCH1. To further understand the mechanisms underlying CLL, Ramsay and colleagues performed exome sequencing in 127 samples and Sanger sequencing in 214 samples from matched tumor and normal blood taken from patients with CLL. This analysis identified protection of telomeres 1 (POT1), which encodes a component of the shelterin complex that is critical for maintenance of telomere integrity, as one of the most frequently mutated genes; somatic, heterozygous mutations in POT1 were found in 3.5% of all samples, including 9% of patients with wild-type immunoglobulin heavy variable cluster (IGHV@), a marker of poor prognosis. Most of these point mutations (9 of 12) were located within the 2 oligonucleotide-/oligosaccharide-binding (OB) folds of the POT1 protein, suggesting that they may destabilize its interaction with telomeric sequences. Indeed, expression of mutant POT1 did not disrupt localization of POT1 or other shelterin proteins to telomeres but prevented POT1 binding to telomeric single-stranded DNA. Consistent with a dominant-negative function of these variants, mutant POT1 proteins promoted telomere elongation independently of telomerase activity and resulted in telomeric aberrations and an elevated frequency of chromosome breaks and fusions. In addition, POT1 mutations were associated with increased telomere-containing sister chromatid fusions and enhanced nuclear alterations in patient-derived CLL cells, further suggesting that POT1 mutations induce telomere fragility via loss of protective telomere capping. Moreover, patients with POT1 mutations exhibited clinical and molecular features of more advanced CLL disease. These findings establish POT1 as the first shelterin gene found to be mutated in human cancer and suggest that it may be a potential driver of genomic instability during CLL progression.

Ramsay AJ, Quesada V, Foronda M, Conde L, Martínez-Trillos A, Villamor N, et al. POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nat Genet 2013 Mar 17 [Epub ahead of print].

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