[JunB Deficiency Leads to a Myeloproliferative Disorder Arising from Hematopoietic Stem Cells]
>>Cell, Vol 119, 431-443, 29 October 2004
JunB Deficiency Leads to a Myeloproliferative Disorder Arising from Hematopoietic Stem Cells
Emmanuelle Passegué,1 Erwin F. Wagner,2 and Irving L. Weissman1
1Institute of Cancer and Stem Cell Biology and Medicine, Departments of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305 USA
2Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria
Correspondence:
Emmanuelle Passegué
650-723-7389 (phone)
650-498-6255 (fax)
passegue@stanford.edu
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.<<
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