PU.1 downregulation in murine radiation-induced acute myeloid leukaemia (AML): from molecular mechanism to human AML.
The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the -14kb SPI1 upstream regulatory element were described previously in human primary AML, although they are rare events. Other mechanisms linked to PU.1 downregulation in human AML include TP53 deletion, FLT3-ITD mutation and the recurrent AML1-ETO [t(8;21)] and PML-RARA [t(15;17)] translocations. This review provides an up-to-date overview on our current understanding of the involvement of PU.1 in the initiation and development of radiation-induced AML, together with recommendations for future murine and human studies.
Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Didcot OX11 ORQ, UK, CRUK & MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Tom
T
Verbiest
Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Didcot OX11 ORQ, UK.
Simon
S
Bouffler
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia and Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Stephen L
SL
Nutt
Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Didcot OX11 ORQ, UK, christophe.badie@phe.gov.uk.
Christophe
C
Badie
D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005720:Gamma Rays / Q000009:adverse effects; D017353:Gene Deletion; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D007953:Leukemia, Radiation-Induced / Q000235:genetics*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014965:X-Rays / Q000009:adverse effects; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051941:fms-Like Tyrosine Kinase 3; D000099232:Proto-Oncogene Protein Spi-1; C495901:TP53 protein, human; C497970:FLT3 protein, human