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Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts
Aruna Kode1, John S Manavalan1, Ioanna Mosialou1
1Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
Nature
|January 17, 2014
Summary
Activating a specific gene in osteoblasts, the bone-forming cells, can trigger acute myeloid leukemia (AML) by disrupting blood cell development through Notch signaling. Inhibiting this pathway shows promise for treating AML.
Area of Science:
- Hematology
- Oncology
- Cell Biology
Background:
- Osteoblast lineage cells influence hematopoietic stem cells and B cell development.
- Osteoblasts have been linked to pre-leukemic conditions, but a direct genetic cause for osteoblast-induced leukemia was unknown.
Purpose of the Study:
- To investigate if a single genetic alteration in osteoblasts can induce leukemia.
- To identify the molecular mechanisms by which osteoblast genetic changes lead to leukemia.
- To explore the therapeutic potential of targeting the identified pathway in leukemia.
Main Methods:
- Induction of activating β-catenin mutation in mouse osteoblasts.
- Analysis of hematopoietic stem cell differentiation and leukemia development.
- Assessment of Notch signaling pathway activation and inhibition.
- Clinical correlation with patient samples exhibiting myelodysplastic syndromes or acute myeloid leukemia.
Main Results:
- Activating β-catenin mutation in osteoblasts altered myeloid and lymphoid progenitor differentiation, causing acute myeloid leukemia with chromosomal aberrations.
- Activated β-catenin upregulated Notch ligand Jagged 1 in osteoblasts, subsequently activating Notch signaling in hematopoietic stem cell progenitors.
- Genetic or pharmacological inhibition of Notch signaling reduced acute myeloid leukemia progression.
- Increased β-catenin signaling in osteoblasts and elevated Notch signaling in hematopoietic cells were observed in 38% of AML/MDS patients.
Conclusions:
- Genetic alterations in osteoblasts can directly induce acute myeloid leukemia.
- The β-catenin-Notch signaling axis in osteoblasts is a key driver of leukemia development.
- Targeting Notch signaling presents a potential therapeutic strategy for acute myeloid leukemia.
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