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Nature. 2014 Feb 13;506(7487):240-4. doi: 10.1038/nature12883. Epub 2014 Jan 15.

Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts.

Author information

1
Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
2
Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
3
Department of Genetics and Development College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
4
Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA.
5
Department of Pathology & Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
6
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.
7
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.
8
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
9
Myelodysplastic Syndromes Center, Columbia University New York, New York 10032, USA.
10
Departments of Medicine Hematology & Oncology Columbia University New York, New York 10032, USA.
11
Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
12
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.

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.

PMID:
24429522
PMCID:
PMC4116754
DOI:
10.1038/nature12883
[Indexed for MEDLINE]
Free PMC Article

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