Publication Date:
2014-01-17
Description:
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 beta-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 beta-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 beta-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116754/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116754/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kode, Aruna -- Manavalan, John S -- Mosialou, Ioanna -- Bhagat, Govind -- Rathinam, Chozha V -- Luo, Na -- Khiabanian, Hossein -- Lee, Albert -- Murty, Vundavalli V -- Friedman, Richard -- Brum, Andrea -- Park, David -- Galili, Naomi -- Mukherjee, Siddhartha -- Teruya-Feldstein, Julie -- Raza, Azra -- Rabadan, Raul -- Berman, Ellin -- Kousteni, Stavroula -- P01 AG032959/AG/NIA NIH HHS/ -- P30 DK063608/DK/NIDDK NIH HHS/ -- R01 AR054447/AR/NIAMS NIH HHS/ -- R01 AR055931/AR/NIAMS NIH HHS/ -- T32 GM082797/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Feb 13;506(7487):240-4. doi: 10.1038/nature12883. Epub 2014 Jan 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Genetics and Development College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA. ; Department of Pathology & Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, New York 10032, USA. ; 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. ; 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. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. ; Myelodysplastic Syndromes Center, Columbia University New York, New York 10032, USA. ; Departments of Medicine Hematology & Oncology Columbia University New York, New York 10032, USA. ; Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24429522" target="_blank"〉PubMed〈/a〉
Keywords:
Anemia/genetics/metabolism/pathology
;
Animals
;
Base Sequence
;
Calcium-Binding Proteins/deficiency/genetics/metabolism
;
Cell Differentiation/genetics
;
Cell Lineage
;
Cell Nucleus/metabolism
;
Cell Transformation, Neoplastic/*genetics/pathology
;
Chromosome Aberrations
;
Female
;
Hematopoietic Stem Cells/metabolism/pathology
;
Humans
;
Intercellular Signaling Peptides and Proteins/deficiency/genetics/metabolism
;
Leukemia, Myeloid, Acute/*genetics/metabolism/*pathology
;
Ligands
;
Male
;
Membrane Proteins/deficiency/genetics/metabolism
;
Mice
;
Mutation/*genetics
;
Myelodysplastic Syndromes/genetics/metabolism/pathology
;
Myeloid Cells/metabolism/pathology
;
Osteoblasts/*metabolism/pathology/secretion
;
Receptors, Notch/metabolism
;
Signal Transduction
;
Tumor Microenvironment/genetics
;
beta Catenin/*genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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