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β-catenin mutation in osteoblasts results in acute myeloid leukaemia

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DOI:10.1038/bonekey.2014.91

Kode et al. demonstrate that a mutation in the gene coding for β-catenin in mice raises expression of jagged 1, the Notch ligand in osteoblasts. This, in turn, activates Notch signaling in hematopoietic stem cell progenitor cells, stimulating them to differentiate into lymphoid and myeloid progenitors and resulting in acute myeloid leukaemia (AML).

Studies on bone marrow biopsies from patients with AML or myelodysplastic syndrome showed a significantly higher incidence of β-catenin gene mutations and a rise in Notch signaling within osteoblasts in patients compared to healthy controls. They argue that their observation that osteoblasts are responsible for the development of cell-autonomous AML, and the subsequent elucidation of the molecular events that underlie this process, highlights the bone marrow niche as a major factor in the development of leukaemias and other cancers of hematological origin.

Editor’s comment: Activation of β-catenin signaling in the osteoblastic-osteocytic lineage is known to result in increased bone formation and decreased bone resorption. The observation that AML develops in mice with a β-catenin activating mutation in their osteoblasts may raise some concerns about developing β-catenin activating drugs, such as sclerostin neutralizing antibodies, for the treatment of bone disorders. However AML has not been reported as a complication of sclerosteosis or Van Buchem disease, and is not known to occur more frequently in Sost or Dkk1 knockout mice.

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