Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia - PubMed (original) (raw)

. 2009 Jan 27;106(4):1187-92.

doi: 10.1073/pnas.0807057106. Epub 2009 Jan 15.

Joshua A Regal, Mark Hills, William T Yewdell, Leandro F Dalmazzo, Marco A Zago, Peter M Lansdorp, Donna Hogge, Stephen J Chanock, Elihu H Estey, Roberto P Falcão, Neal S Young

Affiliations

Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

Rodrigo T Calado et al. Proc Natl Acad Sci U S A. 2009.

Abstract

Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in TERT and TERC genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one TERT gene variant. In the first cohort, 11 patients carried missense TERT gene variants that were not present in controls (P < 0.0001); in the second cohort, TERT mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (n = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (n = 1,110; P = 0.0009). Introduction of TERT mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability.

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Conflict of interest statement

Conflict of interest statement: P.M.L. declares a financial interest in Repeat Diagnostics, a company specializing in leukocyte telomere length measurements using flow-FISH. The other authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

TERT mutations in AML. Schematic domain structure of TERT, indicating 3 major regions: N-terminal, reverse transcriptase motifs, and C-terminal. RID denotes RNA-interaction domain and T telomerase-specific motif. Mutation codon locations and amino acid substitutions caused by mutations are shown. Abbreviations for amino acid residues: A, alanine; E, glutamic acid; H, histidine; K, lysine; M, methionine; R, arginine; T, threonine; V, valine.

Fig. 2.

Fig. 2.

Analysis of TERT gene variants' telomerase enzymatic activity. Telomerase activity of cell lysates made from reconstitution of the wild-type or mutated TERT expression vectors in the telomerase-negative VA13 cell line cotransfected with _TERC_-containing vector was measured by the fluorescent telomeric repeat-amplification protocol (TRAP) assay. Telomerase activity was considered 100% for the wild-type. Each bar (blue) for each vector represents a different transfection experiment and the bar on the top (black) denotes the standard deviation for all experiments for each vector. Telomerase activity in each experiment was corrected for TERT mRNA levels as measured by RT PCR. Cotransfection of wild-type TERT and mutant TERT (R552K Bottom Left and A1062T Bottom Right) at different ratios (indicated below bars) show that telomerase activity is reduced by haploinsufficiency.

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