JunB Deficiency Leads to a Myeloproliferative Disorder Arising from Hematopoietic Stem Cells.pdf

Cell, Vol. 119, 431–443, October 29, 2004, Copyright ?2004 by Cell Press JunB Deficiency Leads to a Myeloproliferative Disorder Arising from Hematopoietic Stem Cells duce mature macrophages and granulocytes (Akashi et al., 1999). Within this developmental scheme, leukemias can Emmanuelle Passegue?,1,* Erwin F. Wagner,2 and Irving L. Weissman1 1Institute of Cancer and Stem Cell Biology now be viewed as aberrant hematopoietic processesand Medicine initiated by rare leukemic stem cells (LSC) that undergoDepartments of Pathology and Developmental an aberrant and poorly regulated process of organogen-Biology esis analogous to that of normal HSC (Reya et al., 2001;Stanford University School of Medicine Passegue? et al., 2003). Since a hallmark of all cancersStanford, California 94305 is the capacity for unlimited self-renewal, it has been2 Research Institute of Molecular Pathology (IMP) proposed, although never directly demonstrated, thatDr. Bohr-Gasse 7 leukemias may be initiated by transforming events thatA-1030 Vienna directly take place in the self-renewing LT-HSC. Alterna-Austria tively, leukemias may also arise from more committed progenitors that have re-acquired the capacity for indefi- nite self-renewing proliferation through accumulated Summary mutations and/or epigenetic changes, as we have re- cently shown for some human acute myeloid leukemia The AP-1 transcription factor JunB is a transcriptional (AML) (Miyamoto et al., 2000) and late-stage human regulator of myelopoiesis. Inactivation of JunB in post- chronic myelogenous leukemia (CML) (Jamieson et al., natal mice results in a myeloproliferative disorder 2004). Identifying the developmental origin of the LSC (MPD) resembling early human chronic myelogenous for each type of leukemia is therefore critical for under- leukemia (CML). Here, we show that JunB regulates standing their respective biology and providing powerful the numbers of hematopoietic stem cells (HSC). JunB diagnostic, prognostic, and therapeut