title: Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia.
abstract: Murine radiation-induced acute myeloid leukaemia (AML) is characterized by loss of one copy of chromosome 2. Previously, we positioned the critical haematopoietic-specific transcription factor PU.1 within a minimally deleted region. We now report a high frequency (>65%) of missense mutation at codon 235 in the DNA-binding Ets domain of PU.1 in murine AML. Earlier studies, outside the context of malignancy, determined that conversion of arginine 235 (R235) to any other amino-acid residue leads to ablation of DNA-binding function and loss of expression of downstream targets. We show that mutation of R235 does not lead to protein loss, and occurs specifically in those AMLs showing loss of one copy of PU.1 (P=0.001, Fisher's exact test). PU.1 mutations were not found in the coding region, UTRs or promoter of human therapy-related AMLs. Potentially regulatory elements upstream of PU.1 were located but no mutations found. In conclusion, we have identified the cause of murine radiation-induced AML and have shown that loss of one copy of PU.1, as a consequence of flanking radiation-sensitive fragile domains on chromosome 2, and subsequent R235 conversion are highly specific to this mouse model. Such a mechanism does not operate, or is extremely rare, in human AML.
authors.affiliation: Cancer Research UK Laboratories, St Mark's Hospital, Harrow, UK.
authors.forename: Nirosha
authors.initials: N
authors.lastname: Suraweera
authors.forename: Emmy
authors.initials: E
authors.lastname: Meijne
authors.forename: John
authors.initials: J
authors.lastname: Moody
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yoshida
authors.forename: Patrick
authors.initials: P
authors.lastname: Pollard
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
authors.forename: Andrew
authors.initials: A
authors.lastname: Riches
authors.forename: Theo
authors.initials: T
authors.lastname: van Laar
authors.forename: Rene
authors.initials: R
authors.lastname: Huiskamp
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D018983:DNA Footprinting; D004195:Disease Models, Animal; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1