Single mutation in bone cells may initiate acute myeloid leukemia
Acute myeloid leukemia (AML) is a blood cancer but, for many patients, the cancer may originate from an unusual source: a mutation in their bone cells. A mutation in osteoblasts, which are a type of bone cell that builds new bone, causes AML in mice. The mutation was found in nearly 40% of patients with AML or myelodysplastic syndrome (MDS), a precursor condition, who were examined as part of the study.
The study was conducted by researchers at Columbia University Medical Center (CUMC) in New York, New York, and published in Nature (2014; doi:10.1038/nature12883). Production of leukemic blood cells in the mice was able to be stopped with a drug that blocked the effects of the osteoblast mutation, suggesting that a similar drug may benefit a large portion of AML and MDS patients.
"If the mutation works the same way in humans, our study suggests practical ways that we may be able to intervene with a drug or an antibody. It may give us a tool for a disease that is rarely curable," said lead investigator Stavroula Kousteni, PhD, of CUMC.
"This paper goes to the heart of bidirectional translational research, as it represents collaboration between institutions, as well as between clinicians and basic scientists," said coauthor Azra Raza, MD, of CUMC. "The Kousteni Lab made the observation that a mutation affecting [beta]-catenin in the bone marrow microenvironment cells of mice can cause leukemia. Clinicians from Memorial Sloan-Kettering Cancer Center in New York, New York, and CUMC then extracted bone marrow samples of patients with MDS and AML from their tissue repositories to confirm a similar pathway in a subset of patients. This incredibly important observation opens the possibilities of novel therapies for these dreaded diseases using nonchemotherapeutic approaches."
AML is one of the most common types of leukemia in adults, with about 15,000 cases diagnosed in the United States each year. The disease progresses rapidly, and only about 25% survive 3 years after diagnosis. MDS is a group of blood disorders diagnosed in about 10,000 people every year in the United States, and many people with MDS eventually develop AML.
Kousteni and colleagues investigated a mouse strain that dies soon after birth from severe blood abnormalities. They found that the disease, which was the same as AML, was caused by a mutation in the beta-catenin gene in the animals' osteoblasts. This mutation affects a protein known as jagged1, which affects Notch proteins.
When they looked at cells from AML and MDS patients, the researchers documented similar changes in beta-catenin, jagged1, and Notch signaling in 38% of the patients.
Though previous studies have shown that osteoblasts and leukemia blasts communicate with each other, this is the first study to clarify how they may do that. This study is also the first to show that a mutation in one cell not only can influence nearby cancer cells, but can cause cancer in another type of cell. Treating cancer by targeting nearby cells is a novel concept in cancer treatment, said Kousteni.