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Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells

Official URL:https://doi.org/10.1038/ng1898
PubMed:View item in PubMed
Creators Name:Steidl, U. and Rosenbauer, F. and Verhaak, R.G.W. and Gu, X. and Ebralidze, A. and Otu, H.H. and Klippel, S. and Steidl, C. and Bruns, I. and Costa, D.B. and Wagner, K. and Aivado, M. and Kobbe, G. and Valk, P.J.M. and Passegue, E. and Libermann, T.A. and Delwel, R. and Tenen, D.G.
Journal Title:Nature Genetics
Journal Abbreviation:Nat Genet
Page Range:1269-1277
Date:November 2006
Keywords:Acute Myeloid Leukemia, Cell Differentiation, Down-Regulation, Genetic Transcription, Granulocytes, Hematopoietic Stem Cell Transplantation, Inbred NOD Mice, Knockout Mice, Neoplastic Cell Transformation, Monocytes, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-jun, SCID Mice, Trans-Activators, Animals, Mice
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.
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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