Telomeres protect chromosome ends from end-to-end fusion and recombination but are gradually eroded with proliferation. Critically short telomeres are repaired by the telomerase complex and mutations in telomerase complex genes (TERT and TERC) are associated with dyskeratosis congenita and acquired aplastic anemia. Telomere shortening eventually results in cell proliferation arrest, apoptosis, or genomic instability, and patients with dyskeratosis congenita and acquired aplastic anemia are at risk for developing leukemia and other malignancies. We therefore investigated whether TERT and TERC gene mutations were associated with acute myeloid leukemia (AML) by screening 100 consecutive Brazilian patients diagnosed with AML (excluding acute promyelocytic leukemia) at the same institution and 198 ethnic-, age-, and sex-matched healthy volunteers. Eight patients carried a non-synonymous TERT gene variant; one was homozygous and five heterozygous for A1062T, one was heterozygous for H412Y, and another was heterozygous for a novel R522K TERT mutation. None of these gene variants was present in matched controls (Fisher’s exact test, P=0.0001). We validated our results by screening an additional 89 AML patients from the MD Anderson Cancer Center, selected based on cytogenetic status and 528 healthy controls. Four of these 89 patients had a non-synonymous TERT gene variant (one homozygous, three heterozygous), an incidence higher than in controls (P=0.028). To further address the higher prevalence of the A1062T gene variant in AML, we screened a total of 1,111 controls, and found a 3.8 times higher A1062T allele frequency in AML than in controls (P=0.002). The germ-line origin of mutations was established by mutation detection in non-hematopoietic tissues and in relatives. Cytogenetics were available for four TERT-mutant patients in the Brazilian cohort: two had inv(16), one had t(5;11)(q35;q13) and del(10)(p15), and another had complex karyotype (including trisomy 8). In the MD Anderson cohort, 2 patients had inv(16) and two had trisomy 8. The incidence of TERT mutations was higher in patients with trisomy 8 (2/10) or inv (16) (2/22) than in other patients (0/57; P =0.02 for trisomy 8 and 0.08 for inv(16) vs. other). Telomere lengths of blast cells were extremely short (median length, 3.1 kb; range, 2.4-5.9 kb). Vectors containing TERT mutants were transfected into VA13 cells and telomerase activity of transfected cell lysates, measured by the fluorescent telomere repeat amplification protocol (TRAP) assay, demonstrated that AML-associated TERT gene variants resulted in significantly reduced telomerase function in comparison to wild-type TERT by haploinsufficiency. Our results indicate that constitutional TERT gene mutations are risk factors for AML. Abnormal telomerase function of hematopoietic stem cells may result in short and dysfunctional telomeres, facilitating genomic instability, aneuploidy, and probably contributing to an early stage of leukemogenesis.

Author notes

Disclosure: No relevant conflicts of interest to declare.