Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts

Aruna Kode; John S Manavalan; Ioanna Mosialou; Govind Bhagat; Chozha V Rathinam; Na Luo; Hossein Khiabanian; Albert Lee; Vundavalli V Murty; Richard Friedman; Andrea Brum; David Park; Naomi Galili; Siddhartha Mukherjee; Julie Teruya-Feldstein; Azra Raza; Raul Rabadan; Ellin Berman; Stavroula Kousteni

doi:10.1038/nature12883

Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts

Nature. 2014 Feb 13;506(7487):240-4. doi: 10.1038/nature12883. Epub 2014 Jan 15.

Authors

Aruna Kode¹, John S Manavalan¹, Ioanna Mosialou¹, Govind Bhagat², Chozha V Rathinam³, Na Luo¹, Hossein Khiabanian⁴, Albert Lee⁴, Vundavalli V Murty⁵, Richard Friedman⁶, Andrea Brum⁷, David Park⁸, Naomi Galili⁹, Siddhartha Mukherjee¹⁰, Julie Teruya-Feldstein⁸, Azra Raza⁹, Raul Rabadan⁴, Ellin Berman¹¹, Stavroula Kousteni¹²

Affiliations

¹ Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
² Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
³ Department of Genetics and Development College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
⁴ Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA.
⁵ Department of Pathology & Institute for Cancer Genetics Irving Cancer Research Center, Columbia University, New York, New York 10032, USA.
⁶ Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center and Department of Biomedical Informatics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.
⁷ 1] Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA [2] Department of Internal Medicine, Erasmus MC, Dr. Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands.
⁸ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
⁹ Myelodysplastic Syndromes Center, Columbia University New York, New York 10032, USA.
¹⁰ Departments of Medicine Hematology & Oncology Columbia University New York, New York 10032, USA.
¹¹ Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
¹² 1] Department of Medicine, Division of Endocrinology, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA [2] Department of Physiology & Cellular Biophysics, College of Physicians & Surgeons, Columbia University, New York, New York 10032, USA.

Abstract

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Anemia / genetics
Anemia / metabolism
Anemia / pathology
Animals
Base Sequence
Calcium-Binding Proteins / deficiency
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism
Cell Differentiation / genetics
Cell Lineage
Cell Nucleus / metabolism
Cell Transformation, Neoplastic / genetics*
Cell Transformation, Neoplastic / pathology
Chromosome Aberrations
Female
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / pathology
Humans
Intercellular Signaling Peptides and Proteins / deficiency
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism
Jagged-1 Protein
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Leukemia, Myeloid, Acute / pathology*
Ligands
Male
Membrane Proteins / deficiency
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mutation / genetics*
Myelodysplastic Syndromes / genetics
Myelodysplastic Syndromes / metabolism
Myelodysplastic Syndromes / pathology
Myeloid Cells / metabolism
Myeloid Cells / pathology
Osteoblasts / metabolism*
Osteoblasts / pathology
Receptors, Notch / metabolism
Serrate-Jagged Proteins
Signal Transduction
Tumor Microenvironment / genetics
beta Catenin / genetics*
beta Catenin / metabolism*

Substances

CTNNB1 protein, mouse
Calcium-Binding Proteins
Intercellular Signaling Peptides and Proteins
JAG1 protein, human
Jag1 protein, mouse
Jagged-1 Protein
Ligands
Membrane Proteins
Receptors, Notch
Serrate-Jagged Proteins
beta Catenin

Associated data

GEO/GSE43242
GEO/GSE51690
SRA/SRP031981

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding