Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts Journal Article

Authors: Kode, A.; Manavalan, J. S.; Mosialou, I.; Bhagat, G.; Rathinam, C. V.; Luo, N.; Khiabanian, H.; Lee, A.; Murty, V. V.; Friedman, R.; Brum, A.; Park, D.; Galili, N.; Mukherjee, S.; Teruya-Feldstein, J.; Raza, A.; Rabadan, R.; Berman, E.; Kousteni, S.
Article 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. © 2014 Macmillan Publishers Limited. All rights reserved.
Journal Title: Nature
Volume: 506
Issue: 7487
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2014-02-13
Start Page: 240
End Page: 244
Language: English
DOI: 10.1038/nature12883
PROVIDER: scopus
PUBMED: 24429522
PMCID: PMC4116754
Notes: Export Date: 3 March 2014 -- CODEN: NATUA -- Source: Scopus
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MSK Authors
  1. Julie T Feldstein
    288 Feldstein
  2. Ellin Berman
    90 Berman
  3. David C Park
    8 Park