1. PU.1 promotes cell cycle exit in the murine myeloid lineage associated with downregulation of E2F1.
- Author
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Ziliotto R, Gruca MR, Podder S, Noel G, Ogle CK, Hess DA, and DeKoter RP
- Subjects
- Acute Disease, Animals, Animals, Newborn, Cell Cycle genetics, Cells, Cultured, Down-Regulation, Doxycycline pharmacology, E2F1 Transcription Factor genetics, Female, Immunoblotting, Interleukin Receptor Common gamma Subunit deficiency, Interleukin Receptor Common gamma Subunit genetics, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Myeloid Cells drug effects, Myeloid Cells transplantation, Oligonucleotide Array Sequence Analysis, Proto-Oncogene Proteins deficiency, Proto-Oncogene Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Spleen cytology, Spleen metabolism, Survival Analysis, Trans-Activators deficiency, Trans-Activators genetics, Transcriptome drug effects, Transcriptome genetics, Cell Cycle physiology, E2F1 Transcription Factor metabolism, Myeloid Cells metabolism, Proto-Oncogene Proteins physiology, Trans-Activators physiology
- 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., (Copyright © 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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