title: Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells.
abstract: Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. Restoration of c-Jun expression in preleukemic cells rescued the PU.1 knockdown-initiated myelomonocytic differentiation block. Lentiviral restoration of JunB at the leukemic stage led to loss of leukemic self-renewal capacity and prevented leukemia in NOD-SCID mice into which leukemic PU.1-knockdown cells were transplanted. Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1-knockdown HSCs and demonstrate that decreased levels of c-Jun and JunB contribute to the development of PU.1 knockdown-induced AML by blocking differentiation and increasing self-renewal. Therefore, examination of disturbed gene expression in HSCs can identify genes whose dysregulation is essential for leukemic stem cell function and that are targets for therapeutic interventions.
authors.affiliation: Harvard Institutes of Medicine, Harvard Medical School and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Frank
authors.initials: F
authors.lastname: Rosenbauer
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
authors.forename: Xuesong
authors.initials: X
authors.lastname: Gu
authors.forename: Alexander
authors.initials: A
authors.lastname: Ebralidze
authors.forename: Hasan H
authors.initials: HH
authors.lastname: Otu
authors.forename: Steffen
authors.initials: S
authors.lastname: Klippel
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Ingmar
authors.initials: I
authors.lastname: Bruns
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.forename: Katharina
authors.initials: K
authors.lastname: Wagner
authors.forename: Manuel
authors.initials: M
authors.lastname: Aivado
authors.forename: Guido
authors.initials: G
authors.lastname: Kobbe
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation; D006098:Granulocytes / Q000166:cytology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009000:Monocytes / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1