title: Leukemogenesis in heterozygous PU.1 knockout mice.
abstract: Most murine radiation-induced acute myeloid leukemias involve biallelic inactivation of the PU.1 gene, with one allele being lost through a radiation-induced chromosomal deletion and the other allele affected by a recurrent point mutation in codon 235 that is likely to be spontaneous. The short latencies of acute myeloid leukemias occurring in nonirradiated mice engineered with PU.1 conditional knockout or knockdown alleles suggest that once both copies of PU.1 have been lost any other steps involved in leukemogenesis occur rapidly. Yet, spontaneous acute myeloid leukemias have not been reported in mice heterozygous for a PU.1 knockout allele, an observation that conflicts with the understanding that the PU.1 codon 235 mutation is spontaneous. Here we describe experiments that show that the lack of spontaneous leukemia in PU.1 heterozygous knockout mice is not due to insufficient monitoring times or mouse numbers or the genetic background of the knockout mice. The results reveal that spontaneous leukemias that develop in mice of the mixed 129S2/SvPas and C57BL/6 background of knockout mice arise by a pathway that does not involve biallelic PU.1 mutation. In addition, the latency of radiation-induced leukemia in PU.1 heterozygous mice on a genetic background susceptible to radiation-induced leukemia indicates that the codon 235 mutation is not a rate-limiting step in radiation leukemogenesis driven by PU.1 loss.
authors: a  Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado.
authors: Paula C
authors: PC
authors: Genik
authors: Irina
authors: I
authors: Vyazunova
authors: Leta S
authors: LS
authors: Steffen
authors: Jeffery W
authors: JW
authors: Bacher
authors: Helle
authors: H
authors: Bielefeldt-Ohmann
authors: Scott
authors: S
authors: McKercher
authors: Robert L
authors: RL
authors: Ullrich
authors: Christina M
authors: CM
authors: Fallgren
authors: Michael M
authors: MM
authors: Weil
authors: F Andrew
authors: FA
authors: Ray
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D003062:Codon; D006579:Heterozygote; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000235:genetics; D007953:Leukemia, Radiation-Induced / Q000209:etiology / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D053842:Microsatellite Instability; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D003062:Codon; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051941:fms-Like Tyrosine Kinase 3; D000099232:Proto-Oncogene Protein Spi-1; C497971:Flt3 protein, mouse