JunB protects against myeloid malignancies by limiting hematopoietic stem cell proliferation and differentiation without affecting self-renewal.
Loss of the JunB/AP-1 transcription factor induces a myeloproliferative disease (MPD) arising from the hematopoietic stem cell (HSC) compartment. Here, we show that junB inactivation deregulates the cell-cycle machinery and increases the proliferation of long-term repopulating HSCs (LT-HSCs) without impairing their self-renewal or regenerative potential in vivo. We found that JunB loss destabilizes a complex network of genes and pathways that normally limit myeloid differentiation, leading to impaired responsiveness to both Notch and TGF-beta signaling due in part to transcriptional deregulation of the Hes1 gene. These results demonstrate that LT-HSC proliferation and differentiation are uncoupled from self-renewal and establish some of the mechanisms by which JunB normally limits the production of myeloid progenitors, hence preventing initiation of myeloid malignancies.
Santaguida
Marianne
M
The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Schepers
Koen
K
King
Bryan
B
Sabnis
Amit J
AJ
Forsberg
E Camilla
EC
Attema
Joanne L
JL
Braun
Benjamin S
BS
Passegué
Emmanuelle
E
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000378:metabolism* / Q000517:prevention & control; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016755:Proto-Oncogene Proteins c-jun; D051880:Receptors, Notch; D016212:Transforming Growth Factor beta