Nature Genetics
- 38, 1269 - 1277 (2006)
Published online: 15 October 2006; | doi:10.1038/ng1898
Essential role of Jun family transcription factors in PU.1 knockdown–induced leukemic stem cellsUlrich Steidl1, Frank Rosenbauer1, 2, Roel G W Verhaak3, Xuesong Gu4, Alexander Ebralidze1, Hasan H Otu4, 5, Steffen Klippel1, Christian Steidl6, Ingmar Bruns7, Daniel B Costa1, Katharina Wagner1, Manuel Aivado4, Guido Kobbe7, Peter J M Valk3, Emmanuelle Passegué8, Towia A Libermann4, Ruud Delwel3 & Daniel G Tenen11
Harvard Institutes of Medicine, Harvard Medical School and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA. 2
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany. 3
Department of Hematology, Erasmus University Medical Center, 3015GE Rotterdam, The Netherlands. 4
Beth Israel Deaconess Medical Center Genomics Center and Bioinformatics Core and Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. 5
Department of Genetics and Bioengineering, Yeditepe University, Istanbul 34755, Turkey. 6
Department of Hematology and Oncology, University of Goettingen, 37075 Goettingen, Germany. 7
Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, 40225 Duesseldorf, Germany. 8
Developmental and Stem Cell Biology Program, University of California, San Francisco, California 94314, USA.
Correspondence should be addressed to Daniel G Tenen dtenen@bidmc.harvard.edu 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
