title: Pten loss in the bone marrow leads to G-CSF-mediated HSC mobilization.
abstract: The phosphatase and tumor suppressor PTEN inhibits the phosphoinositol-3-kinase (PI3K) signaling pathway and plays a key role in cell growth, proliferation, survival, and migration. Pten conditional deletion using MxCre or Scl-CreER(T) leads to splenomegaly and leukemia formation, which occurs after the relocation of normal hematopoietic stem cells (HSCs) from the bone marrow to the spleen. Unexpectedly, dormant HSCs in the bone marrow do not enter the cell cycle upon Pten loss, they do not lose self-renewal activity, and they are not exhausted. Instead, Pten deficiency causes an up-regulation of the PI3K pathway in myeloid cells, but not in HSCs. Strikingly, myeloid cells secrete high levels of G-CSF upon Pten loss, leading to the mobilization of HSCs from the bone marrow and accumulation in the spleen. After deletion of Pten in mice lacking G-CSF, the splenomegaly, myeloproliferative disease, and splenic HSC accumulation are rescued. Our data show that although PTEN has little if any role in normal HSCs, it is essential to prevent overt G-CSF production by myeloid and stromal cells which otherwise causes HSCs to relocate to the spleen followed by lethal leukemia initiation.
authors.affiliation: Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Melania
authors.initials: M
authors.lastname: Tesio
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Oser
authors.forename: Irène
authors.initials: I
authors.lastname: Baccelli
authors.forename: William
authors.initials: W
authors.lastname: Blanco-Bose
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Göthert
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
mesh_terms: D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000201:enzymology*; D016207:Cytokines / Q000378:metabolism; D017353:Gene Deletion; D016179:Granulocyte Colony-Stimulating Factor / Q000172:deficiency / Q000378:metabolism*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D019426:Integrases / Q000378:metabolism; D051379:Mice; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D016179:Granulocyte Colony-Stimulating Factor; D051057:Proto-Oncogene Proteins c-akt; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse