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Alterations in β-catenin signalling in osteoblasts can cause AML
DOI:10.1038/bonekey.2014.48
Kode et al. followed up the observation that mice with a β-catenin activating mutation in osteoblasts die before the age of 6 weeks and exhibit anaemia and other signs indicative of acute myeloid leukaemia (AML).
By transplanting bone marrow cells from these mice into wild-type mice treated with lethal radiation, the researchers were able to show that the recipients developed AML. They narrowed down the cells responsible to long-term repopulating haematopoietic stem cell progenitors (LT-HSCs). They concluded that induction of AML in the mice with mutated β-catenin was due to a defect in niche signals in the bone marrow osteoblasts only.
A search for the genes within osteoblasts that are targets for β−catenin identified jagged 1, the Notch ligand. Genetic manipulation of mice to remove one of the jagged 1 alleles, and so reduce Notch signalling in osteoblasts, resulted in mice that were still osteopetrotic but that did not show any signs of AML or premature death.
Editor’s comment: This study demonstrates that an activating mutation of β-catenin in mouse osteoblasts stimulates jagged 1 expression in osteoblasts, leading to the activation of Notch signalling in haematopoietic stem cells and the development of AML. This report identifies a single genetic alteration in osteoblasts that can induce AML that may warrant follow up as a novel therapeutic target.
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