by ecancer reporter Janet Fricker

Mutations in mice osteoblasts appear to contribute to the development of acute myeloid leukaemia (AML), report US researchers in Nature.

While genetic changes within osteoblasts have been implicated as having a role in triggering leukaemia, the exact pathways have remained unclear.

In the current study Stavroula Kousteni and colleagues, from Columbia University, New York, demonstrated that the activation of mutations in the beta-catenin gene in osteoblasts were sufficient to initiate the development of AML.

The starting point for their  study was the finding that mice expressing a constitutively active b-catenin allele in osteoblasts, referred to as Ctnnb1CAosb were are osteopetrotic (a syndrome characterised by failure of osteoblasts to resorb bone) and died within six weeks of birth.

Further study revealed the mice were anaemic at two weeks, with peripheral blood monocytosis, neutrophilia, lymphocytopenia and thrombocytopenia.

Their cellular abnormalities fulfilled the AML diagnosis criteria and shared features with human AML.

The investigators went on to show that transplantation of bone marrow cells from Ctnnb1CAosb leukemic mice into lethally irradiated wild-type recipients induced AML.

Such work demonstrated that osteoblasts were responsible for AML development.

Through microarray analysis b-catenin target genes in the osteoblasts were identified as the candidate genes for haematopoietic stem cell regulation.

One particular gene - Notch ligand jagged 1 - fulfilled four criteria: it acted on adjacent cells, activated a pathway in which many targets are increased in the array, has been implicated in haematopoiesis and was regulated transcriptionally by b-catenin.

To determine if jagged 1 in osteoblasts contributed to AML development in Ctnnb1CAosb mice, the investigators removed one allele of jagged 1 in osteoblasts.

The outcome of this genetic manipulation was the prevention of AML development.

The mice survived and were healthy for the entire time observed even though they remained osteopetriotic.

Similarly, pharmacological inhibition of Notch signalling (with a csecretase inhibitor) reversed haematopoietic deregulation and myeloid expansion in blood, marrow and spleen and reversed AML in Ctnnb1CAosb mice without affecting osteopetrosis.

To assess the relevance of their findings to humans, the investigators examined activation of b-catenin signalling in bone marrow biopsies taken from 107 MDS and AML patients.

Altogether they found that 38.3% of patients showed nuclear localization of b-catenin in osteoblasts, and that notch activity was increased in haematopoietic cells from the same patients, but not in healthy controls.

“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,” write the authors.

Reference:

A Kode, J Manavalan, I Mosialou, et al. Leukaemogenesis induced by an activating b-catein mutation in osteoblasts. Nature. doi:10.1038/nature12883