JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells.
The AP-1 transcription factor JunB is a transcriptional regulator of myelopoiesis. Inactivation of JunB in postnatal mice results in a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML). Here, we show that JunB regulates the numbers of hematopoietic stem cells (HSC). JunB overexpression decreases the frequency of long-term HSC (LT-HSC), while JunB inactivation specifically expands the numbers of LT-HSC and granulocyte/macrophage progenitors (GMP) resulting in chronic MPD. Further, we demonstrate that junB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD and that only junB-deficient LT-HSC are capable of transplanting the MPD to recipient mice. These results demonstrate a stem cell-specific role for JunB in normal and leukemic hematopoiesis and provide experimental evidence that leukemic stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of MPD.
Passegué
Emmanuelle
E
Institute of Cancer and Stem Cell Biology and Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. passegue@stanford.edu
Wagner
Erwin F
EF
Weissman
Irving L
IL
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D016755:Proto-Oncogene Proteins c-jun