Common Leukemia Induced by Single Mutation in Osteoblasts

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, called osteoblasts.

Cells of the osteoblast lineage affect the homing and the number of long-term repopulating hematopoietic stem cells, hematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis.

Scientists at the Columbia University Medical Center (New York, NY, USA) and colleagues from other institutes found that a mutation in the osteoblasts, which build new bone, causes AML in mice. Bone marrow biopsies from patients with AML and myelodysplastic syndromes (MDS) were consecutively obtained from 2000 to 2008. Using many different techniques the investigators found that AML was caused by a mutation in the β-catenin gene in the animals' osteoblasts.

The mutation leads to cancer in adjacent bone-marrow stem cells through a series of events. First, the mutated β-catenin protein moves from its normal location on the exterior of the osteoblast to the cell's nucleus, where it turns on production of a protein called jagged1. Jagged1 proteins are then transported to the osteoblast's exterior membrane, where they can bind to Notch proteins, which activate signaling pathways, on neighboring bone-marrow stem cells. When this happens, Notch transmits signals inside the bone-marrow stem cells that ultimately transform the cells to leukemia. When the investigators looked at cells from AML and MDS patients, the scientists documented similar changes in β-catenin, jagged1, and Notch signaling in 38% of the patients.

Azra Raza, MD, a coauthor of the study said, “After the observation that a mutation affecting β-catenin in the bone marrow microenvironment cells of mice can cause leukemia, the team 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 non-chemotherapeutic approaches.”

AML is one of the most common types of leukemia in adults, with about 15,000 cases diagnosed in the USA each year. The disease progresses rapidly, and only about 25% survive three years after diagnosis. MDS is a group of blood disorders diagnosed in about 10,000 people in the USA each year and many people with MDS eventually develop AML. The study was published on January 15, 2014, in the journal Nature.

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