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

Ulrich Steidl, Frank Rosenbauer, Roel G.W. Verhaak, Xuesong Gu, Alexander Ebralidze, Hasan H. Otu, Steffen Klippel, Christian Steidl, Ingmar Bruns, Daniel B. Costa, Katharina Wagner, Manuel Aivado, Guido Kobbe, Peter J.M. Valk, Emmanuelle Passegué, Towia A. Libermann, Ruud Delwel, Daniel G. Tenen

Research output: Contribution to journalArticle

131 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1269-1277
Number of pages9
JournalNature Genetics
Volume38
Issue number11
DOIs
StatePublished - Nov 23 2006
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Steidl, U., Rosenbauer, F., Verhaak, R. G. W., Gu, X., Ebralidze, A., Otu, H. H., Klippel, S., Steidl, C., Bruns, I., Costa, D. B., Wagner, K., Aivado, M., Kobbe, G., Valk, P. J. M., Passegué, E., Libermann, T. A., Delwel, R., & Tenen, D. G. (2006). Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. Nature Genetics, 38(11), 1269-1277. https://doi.org/10.1038/ng1898