title: FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice.
abstract: Osteoblasts, the bone forming cells, affect self-renewal and expansion of hematopoietic stem cells (HSCs), as well as homing of healthy hematopoietic cells and tumor cells into the bone marrow. Constitutive activation of β-catenin in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to initiate the development of acute myeloid leukemia (AML) in mice. We show here that Notch1 is the receptor mediating the leukemogenic properties of osteoblast-activated β-catenin in HSCs. Moreover, using cell-specific gene inactivation mouse models, we show that FoxO1 expression in osteoblasts is required for and mediates the leukemogenic properties of β-catenin. At the molecular level, FoxO1 interacts with β-catenin in osteoblasts to induce expression of the Notch ligand, Jagged-1. Subsequent activation of Notch signaling in long-term repopulating HSC progenitors induces the leukemogenic transformation of HSCs and ultimately leads to the development of AML. These findings identify FoxO1 expressed in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/activated β-catenin interaction results in AML. These observations support the notion that the bone marrow niche is an instigator of leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kode
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: I
authors.initials: I
authors.lastname: Mosialou
authors.affiliation: Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Manavalan
authors.affiliation: Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: C V
authors.initials: CV
authors.lastname: Rathinam
authors.affiliation: Biomedical Informatics Shared Resource, Department of Biomedical Informatics, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.|Department of Pathology, Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, NY, USA.
authors.forename: G
authors.identifier: http://orcid.org/0000-0001-6250-048X
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Berman
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kousteni
mesh_terms: D000740:Anemia / Q000209:etiology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D015470:Leukemia, Myeloid, Acute / Q000209:etiology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D010006:Osteoblasts / Q000502:physiology*; D051880:Receptors, Notch / Q000502:physiology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D051176:beta Catenin / Q000502:physiology*
chemical_list: C495267:CTNNB1 protein, mouse; D002135:Calcium-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051176:beta Catenin