Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

Rodrigo T. Calado, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1187-1192
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number4
DOIs
StatePublished - Jan 27 2009
Externally publishedYes

Fingerprint

Telomerase
Acute Myeloid Leukemia
Mutation
Genes
Telomere
Stem Cells
Dyskeratosis Congenita
Bone Marrow
Haploinsufficiency
Germ-Line Mutation
Aplastic Anemia
Genomic Instability
Cytogenetics
Genetic Recombination
DNA Damage
Leukemia
Chromosomes
Cell Proliferation
DNA

Keywords

  • Cancer
  • Dyskeratosis congenita
  • Risk factor
  • Telomere

ASJC Scopus subject areas

  • General

Cite this

Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. / Calado, Rodrigo T.; Regal, Joshua A.; Hills, Mark; Yewdell, William T.; Dalmazzo, Leandro F.; Zago, Marco A.; Lansdorp, Peter M.; Hogge, Donna; Chanock, Stephen J.; Estey, Elihu H.; Falcão, Roberto P.; Young, Neal S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 4, 27.01.2009, p. 1187-1192.

Research output: Contribution to journalArticle

Calado, RT, Regal, JA, Hills, M, Yewdell, WT, Dalmazzo, LF, Zago, MA, Lansdorp, PM, Hogge, D, Chanock, SJ, Estey, EH, Falcão, RP & Young, NS 2009, 'Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 4, pp. 1187-1192. https://doi.org/10.1073/pnas.0807057106
Calado, Rodrigo T. ; Regal, Joshua A. ; Hills, Mark ; Yewdell, William T. ; Dalmazzo, Leandro F. ; Zago, Marco A. ; Lansdorp, Peter M. ; Hogge, Donna ; Chanock, Stephen J. ; Estey, Elihu H. ; Falcão, Roberto P. ; Young, Neal S. / Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 4. pp. 1187-1192.
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T1 - Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

AU - Calado, Rodrigo T.

AU - Regal, Joshua A.

AU - Hills, Mark

AU - Yewdell, William T.

AU - Dalmazzo, Leandro F.

AU - Zago, Marco A.

AU - Lansdorp, Peter M.

AU - Hogge, Donna

AU - Chanock, Stephen J.

AU - Estey, Elihu H.

AU - Falcão, Roberto P.

AU - Young, Neal S.

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N2 - 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.

AB - 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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KW - Dyskeratosis congenita

KW - Risk factor

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