Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts
| Autor: | Andrea Brum, Hossein Khiabanian, David C. Park, Ioanna Mosialou, Richard A. Friedman, Aruna Kode, Naomi Galili, Raul Rabadan, Ellin Berman, Stavroula Kousteni, Govind Bhagat, Julie Teruya-Feldstein, Chozha V. Rathinam, John S. Manavalan, Na Luo, Albert Lee, Vundavalli V. Murty, Siddhartha Mukherjee, Azra Raza |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Myeloid Carcinogenesis Cellular differentiation Ligands Mice hemic and lymphatic diseases Pathology Tumor Microenvironment Myeloid Cells Serrate-Jagged Proteins beta Catenin Multidisciplinary Receptors Notch Catenins Anemia Cell Differentiation Research Highlight 3. Good health Cell biology Haematopoiesis Leukemia Myeloid Acute medicine.anatomical_structure Cell Transformation Neoplastic Medicine Intercellular Signaling Peptides and Proteins Female Stem cell Signal Transduction Notch signaling pathway Biology Article medicine Animals Humans Cell Lineage Lymphopoiesis Progenitor cell Cell Nucleus Chromosome Aberrations Osteoblasts Base Sequence Calcium-Binding Proteins Membrane Proteins Hematopoietic Stem Cells Leukemia--Etiology Myelodysplastic Syndromes Mutation Jagged-1 Protein |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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