title: PU.1 promotes cell cycle exit in the murine myeloid lineage associated with downregulation of E2F1.
abstract: Acute myeloid leukemia (AML) is characterized by increased proliferation and reduced differentiation of myeloid lineage cells. AML is frequently associated with mutations or chromosomal rearrangements involving transcription factors. PU.1 (encoded by Sfpi1) is an E26 transformation-specific family transcription factor that is required for myeloid differentiation. Reduced PU.1 levels, caused by either mutation or repression, are associated with human AML and are sufficient to cause AML in mice. The objective of this study was to determine whether reduced PU.1 expression induces deregulation of the cell cycle in the myeloid lineage. Our results showed that immature myeloid cells expressing reduced PU.1 levels (Sfpi1(BN/BN) myeloid cells) proliferated indefinitely in cell culture and expanded in vivo. Transplantation of Sfpi1(BN/BN) cells induced AML in recipient mice. Cultured Sfpi1(BN/BN) cells expressed elevated messenger RNA transcript and protein levels of E2F1, an important regulator of cell cycle entry. Restoration of PU.1 expression in Sfpi1(BN/BN) myeloid cells blocked proliferation, induced differentiation, and reduced E2F1 expression. Taken together, these data show that PU.1 controls cell cycle exit in the myeloid lineage associated with downregulation of E2F1 expression.
authors: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors: Rachel
authors: R
authors: Ziliotto
authors: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors: Marek R
authors: MR
authors: Gruca
authors: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
authors: Shreya
authors: S
authors: Podder
authors: Department of Research, Shriners Hospital for Children, Cincinnati, OH, USA.
authors: Greg
authors: G
authors: Noel
authors: Department of Research, Shriners Hospital for Children, Cincinnati, OH, USA; Department of Surgery, The University of Cincinnati, Cincinnati, OH, USA.
authors: Cora K
authors: CK
authors: Ogle
authors: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Robarts Research Institute, Western University, London, Ontario, Canada.
authors: David A
authors: DA
authors: Hess
authors: Department of Microbiology and Immunology and the Centre for Human Immunology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Department of Oncology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. Electronic address: rdekoter@uwo.ca.
authors: Rodney P
authors: RP
authors: DeKoter
mesh_terms: D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D004318:Doxycycline / Q000494:pharmacology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015151:Immunoblotting; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016019:Survival Analysis; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D004318:Doxycycline; D050687:E2F1 Transcription Factor; D053631:Interleukin Receptor Common gamma Subunit; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C493754:E2f1 protein, mouse; C507942:Il2rg protein, mouse