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Discovery of a germ line mutation in shelterin complex associated with familial CLL

Nov 16, 2016

In November 2016, Helen Speedyfrom The Institute of Cancer Research, London, UK,and colleagues reported the results of the whole exome sequencing of 66 CLL families from the UK in Blood.


  • Identified in 4 CLL families germ line loss-of-function mutations in POT1 that co-segregated with CLL
  • POT1 is a member of the six component shelterin complex, which together regulates telomeres
  • Germ line mutations found in other shelterin complex members; TERF2IP and ACD in 3 CLL families
  • POT1 p.Gln376Arg mutation associated with a 3.61-fold increase in CLL risk (P=0.009)

The authors concluded by stating that their data shows that components of the shelterin complex are associated with CLL risk. Additionally, as telomeric dysregulation has been identified as a potential therapeutic target in CLL, the identification of these mutations may inform future treatment and disease management.

In an accompanying commentary, Renée Beekmanand Elias Campostated that a remaining important question was, given that Speedy et al. showed that telomeric length was not affected by shelterin status, how is CLL development influenced by the shelterin complex? More work will need to be performed in this complex field in order to better understand the relationship between the shelterin complex and risk of CLL.

Abstract:Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P = .009). This study further highlights telomere dysregulation as a key process in CLL development.

  1. Speedy H.E. et al. Germline mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia. Blood. 2016 Nov 10; 128(19):2319–2326. doi:10.1182/blood-2016-01-695692.
  2. Beekman R. & Campo E. Shelterins, a genetic crossroad in CLL. Blood. 2016 Nov 10; 128(19):2279–2280. doi:10.1182/blood-2016-09-735688.