POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults. We have analyzed exome sequencing data from 127 individuals with CLL and Sanger sequencing data from 214 additional affected individuals, identifying recurrent somatic mutations in POT1 (encoding protection of telomeres 1) in 3.5% of the cases, with the frequency reaching 9% when only individuals without IGHV@ mutations were considered. POT1 encodes a component of the shelterin complex and is the first member of this telomeric structure found to be mutated in human cancer. Somatic mutation of POT1 primarily occurs in gene regions encoding the two oligonucleotide-/oligosaccharide-binding (OB) folds and affects key residues required to bind telomeric DNA. POT1-mutated CLL cells have numerous telomeric and chromosomal abnormalities that suggest that POT1 mutations favor the acquisition of the malignant features of CLL cells. The identification of POT1 as a new frequently mutated gene in CLL may facilitate novel approaches for the clinical management of this disease.

Chronic lymphocytic leukemia: Time to go past genomics?

“…Among hematological malignancies, the numbers of genetic and genomic aberrations in CLL are slightly higher than in acute leukemia but lower than in diffuse large B-cell lymphoma (DLBCL) and myeloma. Massive sequencing studies have now analyzed more than one thousand CLL samples [4][5][6][7][8][9][10][11][12], first confirming known-CLL associated alterations (mutations in key tumor suppressor genes such as TP53 and ATM) but also identifying recurrently targeted genes that had not been previously described in CLL. No unifying mutation has been identified, unlike hairy-cell leukemia (HCL) or Waldenstr€ om macroglobulinemia (WM) in which BRAF V600E [37] and MYD88 L265P [38] mutations, respectively, are present in virtually all cases.…”

“…Comparison of germ line (fibroblast or T-cell) and tumor genome sequencing counted an average of 20 mutations with coding consequences per sample [4][5][6][7][8][9][10][11][12]. Analyses of the mutation signatures point at two putative forces at play.…”

“…Recently, several large-scale studies of massive sequencing (NGS) [4][5][6][7][8][9][10][11][12] have provided a more detailed genetic landscape of CLL. However, none of the identified gene mutations is observed in more than 20% of CLL patients, underscoring the heterogeneity of CLL.…”

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

“…ATM, NOTCH1, SF3B1, TP53) 13,14 with a long tail of genes altered in <5% of cases (e.g. CHD2 15 , MED12 16 , NFKBIE 17 , POT1 18 , RPS15 19 , SETD2 20 , XPO1 21 ). Though integration of molecular information has been proposed to improve classical risk stratification models [22][23][24][25] , a substantial proportion of patients with a dismal clinical course will not be captured by these algorithms, hence indicating a need to identify additional molecular markers of disease aggressiveness.…”

Chronic lymphocytic leukemia: looking into the dark side of the genome

“…The first genomic studies stemming from these initiatives identified recurrently mutated genes such as NOTCH1, SF3B1, TP53, BIRC3, POT1 and CHD2. [5][6][7][8][9][10] Notably, these studies also revealed a marked genetic heterogeneity of CLL, with most genes mutated at frequencies lower than 5%. These new analyses presented by the ICGC and TCGA consortia, with cohort sizes of 506 and 538 CLL samples, are expected to saturate candidate CLL gene discovery for genes mutated in 5% of patients, providing 94 and 61% accuracy to detect genes mutated in 3 and 2% of patients, respectively.…”