title: Defining the pathogenic role of telomerase mutations in myelodysplastic syndrome and acute myeloid leukemia.
abstract: The primary pathology in many cases of myelodysplasia (MDS) and acute myeloid leukemia (AML) remains unknown. In some cases, two or more affected members have been identified in the same family. To date, mutations in two genes have been directly implicated: the hematopoietic transcription factors RUNX1 (runt-related transcription factor 1) and CEBPA (CCATT-box enhancer binding protein alpha). However, there are also other familial cases of MDS/AML where the genetic basis remains unknown. Both MDS, and to a lesser extent AML, have been observed in cases of the bone marrow failure syndrome dyskeratosis congenita, in which telomerase mutations have been identified. Recently, an increased incidence of telomerase reverse transcriptase mutations has been reported in a series of de novo AML. We have now identified novel mutations in the telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT) within 4 of 20 families presenting with familial MDS/AML. Functional analysis has demonstrated that all mutations adversely impact on telomerase activity in vitro, and affected individuals have short telomeres. These families, in conjunction with a review of previously published cases, help to further define the pathological role of telomerase mutations in MDS/AML and have implications for the biology, treatment and screening regimen of de novo cases.
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Barts and The London Children's Hospital, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Kirwan
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Anna
authors.initials: A
authors.lastname: Marrone
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Walne
authors.forename: Richard
authors.initials: R
authors.lastname: Beswick
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.forename: Richard
authors.initials: R
authors.lastname: Kelly
authors.forename: Andrew
authors.initials: A
authors.lastname: Stewart
authors.forename: David
authors.initials: D
authors.lastname: Bowen
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Schonland
authors.forename: Annika Maria
authors.initials: AM
authors.lastname: Whittle
authors.forename: Anthony
authors.initials: A
authors.lastname: McVerry
authors.forename: Maria
authors.initials: M
authors.lastname: Gilleece
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000595:Amino Acid Sequence; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D010375:Pedigree; D012313:RNA / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*
chemical_list: C422952:telomerase RNA; D012313:RNA; C509186:TERT protein, human; D019098:Telomerase