Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells.
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.
Steidl
Ulrich
U
Harvard Institutes of Medicine, Harvard Medical School and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
Rosenbauer
Frank
F
Verhaak
Roel G W
RG
Gu
Xuesong
X
Ebralidze
Alexander
A
Otu
Hasan H
HH
Klippel
Steffen
S
Steidl
Christian
C
Bruns
Ingmar
I
Costa
Daniel B
DB
Wagner
Katharina
K
Aivado
Manuel
M
Kobbe
Guido
G
Valk
Peter J M
PJ
Passegué
Emmanuelle
E
Libermann
Towia A
TA
Delwel
Ruud
R
Tenen
Daniel G
DG
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
D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1