Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

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 telomerasedeficient 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.risk factor ͉ telomere ͉ dyskeratosis congenita ͉ cancer

Telomere length is inherited with resetting of the telomere set-point

“…Telomere length in peripheral blood lymphocytes (PBLs) was analyzed in three families with TERT mutations and a history of aplastic anemia (17,18). Telomere length was very short as measured by flow-FISH for individuals with TERT mutations from these three families, with all 15 below the 10th percentile for normal controls and 13 of 15 below the first percentile for controls ( Fig.…”

“…Telomere length of 17th generation Tert +/− mice g (17), as determined by flow-FISH, was reduced to 52% of the mean fluorescence intensity of B6 mice. The calculated actual telomere lengths of B6 and Tert +/− /g(17) mice also were compared and similarly demonstrated a 54% reduction in telomere length in Tert +/− /g (17) mice (Fig.…”

Acquired TERT promoter mutations stimulate TERT transcription in mantle cell lymphoma

“…Telomeres shorten with mitotic cell division and telomere excessive attrition predisposes cells to chromosomal aberrations and malignant transformation, including hematologic malignancies [4,5]. The shelterin complex (TRF1, TRF2, TIN2, RAP1, TPP1, and POT1) comprises a group of proteins coating telomeres and regulates telomere length (TL) by modulating telomerase activity [6].…”

TERTrific hormones promote hematopoiesis

“…While a large part of the GVT effect is related to the occurrence of GVHD, there is clear evidence that a selective effect of donor adaptive immunity on tumor cells can occur after allo-HSCT even without GVHD. 3 This specific GVT effect is thought to be either directed against antigens with a tissue-restricted distribution (on hematopoietic cells in case of hematologic malignancies) or specifically preferentially expressed on tumor cells. 4 Minor histocompatibility antigens (mHAgs) are polymorphic peptides encoded by genes located throughout the human genome, which can be presented by the major histocompatibility complex (MHC) molecules and recognized as a foreign antigen by T lymphocytes of a certain donor.…”

“…Mutations in several telomere maintenance proteins, including TERT, result in a genetic marrow failure syndrome, dyskeratosis congenita, and have been shown to increase the risk of developing acquired bone marrow failure and acute myeloid leukemia. 3,4 In sum, these observations highlight a critical role for telomere maintenance and intact TERT function in the regulation of hematopoiesis.…”