Osteoblast-Specific Genetic Alterations Can Induce AML

Osteoblasts are key facilitators of hematopoietic stem cell (HSC) homing, mobilization, and lineage specification. Previous studies have connected osteoblasts to preleukemic characteristics in mice, but it is unclear whether they play a direct causative role in leukemogenesis. Kode and colleagues sought to determine whether a single genetic alteration in osteoblasts could induce leukemia by generating mice expressing a constitutively active β-catenin allele in osteoblasts (Ctnnb1^CAosb). Prior to death by 6 weeks, Ctnnb1^CAosb mice developed hematopoietic dysfunction indicative of acute myeloid leukemia (AML), with splenic myeloid cells harboring recurrent cytogenetic abnormalities orthologous to those commonly observed in human AML and myelodysplastic syndrome (MDS). Transplantation of bone marrow cells from Ctnnb1^CAosb mice into lethally irradiated recipients induced AML and early lethality, with long-term repopulating HSCs (LT-HSC) acting as leukemia-initiating cells. Strikingly, transplantation of wild-type bone marrow cells to lethally irradiated Ctnnb1^CAosb recipients also resulted in lethal AML, providing support for a role of osteoblasts in leukemogenesis. Microarray profiling to identify osteoblast β-catenin targets that might alter HSC function revealed that the Notch ligand jagged 1 (Jag1) was highly upregulated in Ctnnb1^CAosb osteoblasts in association with increased Notch signaling in LT-HSCs. Deletion of one Jag1 allele in osteoblasts or pharmacologic inhibition of Notch signaling prevented AML development in Ctnnb1^CAosb mice, suggesting that osteoblast-induced Notch signaling in HSCs drives AML formation. Consistent with these findings, 41 of 107 (38%) bone marrow biopsies from patients with AML or MDS showed increased β-catenin nuclear localization in osteoblasts and increased Notch signaling in hematopoietic cells, whereas nuclear β-catenin staining and Notch pathway activation were not observed in osteoblasts and hematopoietic cells of healthy controls. Together, these findings establish that genetic alterations in osteoblasts can drive the malignant transformation of myeloid progenitors, a finding that may have implications for the treatment of AML.

Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, et al. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 2014 Jan 15 [Epub ahead of print].

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