title: Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts.
abstract: Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.
authors.affiliation: Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Aruna
authors.initials: A
authors.lastname: Kode
authors.affiliation: Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Manavalan
authors.affiliation: Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Mosialou
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Department of Genetics and Development College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Chozha V
authors.initials: CV
authors.lastname: Rathinam
authors.affiliation: Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.affiliation: Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Pathology & Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
authors.forename: Vundavalli V
authors.initials: VV
authors.lastname: Murty
authors.affiliation: Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Friedman
authors.affiliation: 1] Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA [2] Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brum
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: David
authors.initials: D
authors.lastname: Park
authors.affiliation: Myelodysplastic Syndromes Center, Columbia University New York, New York 10032, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Galili
authors.affiliation: Departments of Medicine Hematology & Oncology Columbia University New York, New York 10032, USA.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.affiliation: Myelodysplastic Syndromes Center, Columbia University New York, New York 10032, USA.
authors.forename: Azra
authors.initials: A
authors.lastname: Raza
authors.affiliation: Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
authors.forename: Ellin
authors.initials: E
authors.lastname: Berman
authors.affiliation: 1] Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA [2] Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kousteni
mesh_terms: D000740:Anemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051176:beta Catenin