Common blood cancer may be initiated by single mutation in bone cells

January 22, 2014
Common blood cancer may be initiated by single mutation in bone cells
Mutated beta-catenin in bone cells may cause up to 40 percent of acute myeloid leukemia cases. In the cells of healthy subjects (left), beta catenin proteins (red dots) sit along the outer edges of the cell. In approximately 40 percent of AML patients (right), abnormal beta-catenin proteins (red dots) move into the cell interior; in mouse models, this movement sets cancer-causing changes into motion. Credit: Dr. Aruna Kode/Kousteni lab, Columbia University Medical Center.

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.

In a study published today in the of Nature, researchers at Columbia University Medical Center (CUMC) found that a mutation in the called osteoblasts, which build new bone, causes AML in mice. The mutation was found in nearly 40 percent of patients with AML or (MDS), a precursor condition, who were examined as part of the study.

The researchers were able to stop production of leukemic blood cells in the mice 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 the study's lead investigator Stavroula Kousteni, PhD, associate professor of medical sciences in medicine and physiology & cellular biophysics at CUMC.

"This paper goes to the heart of bi-directional translational research, as it represents collaboration between institutions, as well as between clinicians and basic scientists," said Azra Raza, MD, director of CUMC's MDS Center and a co-author of the study. "The Kousteni Lab made the observation that a mutation affecting b-catenin in the bone marrow microenvironment cells of mice can cause leukemia. Clinicians from Memorial Sloan-Kettering 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 non-chemotherapeutic approaches."

AML is one of the most common types of leukemia in adults, with about 15,000 cases diagnosed in the U.S. each year. The disease progresses rapidly, and only about 25 percent survive three years after diagnosis. MDS is a group of blood disorders diagnosed in about 10,000 people in the U.S. each year. Many people with MDS eventually develop AML.

Mutation of beta-catenin gene in osteoblasts causes AML in mice

In the current study, Dr. 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.

The mutation leads to cancer in adjacent bone-marrow stem cells through a series of events. First, the mutated beta-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 shipped 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 that ultimately transform the cells to leukemia.

When they looked at cells from AML and MDS patients, the researchers documented similar changes in beta-catenin, jagged1, and Notch signaling in 38 percent of the patients.

"Previous studies have shown that osteoblasts and leukemia blasts communicate with each other," said Ellin Berman, MD, a co-author of the study and leukemia clinician at Memorial Sloan-Kettering Cancer Center. "This study is the first to clarify exactly how that may happen."

New concept in cancer treatment

This study is the first to show that a mutation in one cell not only can influence nearby but can cause cancer in another type of cell. Treating cancer by targeting nearby cells is a novel concept in cancer treatment, says Dr. Kousteni. "You're treating a cancer by targeting a cell that doesn't change— instead of chasing the cancer cells, which constantly mutate and change.

"In AML, targeting jagged1 may stop the creation of new malignant cells; it would likely be used in combination with cytotoxic therapy. The first drug would prevent the emergence of new malignant cells; the second would eradicate the existing ones.

"The findings in this paper have crucial implications for our patients," said Siddhartha Mukherjee, MD, PhD, assistant professor of medicine at Columbia and a co-author of the study. "We have a growing armamentarium of drugs that target and kill cancer cells. But if cancer arises because of an interaction between a cell and its environment, we could potentially target that environment as well. Indeed, the cancer 'microenvironment' might be more amenable to drug therapy, as it likely has less of a propensity to mutate. At Columbia's MDS Center, we have been banking tissue samples of this cancer microenvironment, in addition to cancer cells. We hope to unleash all the resources now deployed on cancer to learn about, and target, microenvironments,- the 'homes' that cancers grow in."

Explore further: Researchers discover mechanism controlling the development of myelodysplastic

More information: The paper is titled "Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts."

Related Stories

Researchers discover mechanism controlling the development of myelodysplastic

December 17, 2013
Researchers at the Moffitt Cancer Center have discovered a control mechanism that can trigger the development of myelodysplastic syndromes (MDS), a group of blood cancers. This finding may lead to therapies capable of preventing ...

Compound that could prevent acute blood cancer relapse identified

April 17, 2013
Researchers from the RIKEN Center for Integrative Medical Sciences in Japan report today that they have identified a compound that could be used as a new treatment to prevent relapse in acute myeloid leukemia patients.

Targeting errant immune system enzyme kills myelodysplastic cells

July 8, 2013
Scientists have successfully targeted a malfunctioning immune system enzyme to kill diseased cells from patients with myelodysplastic syndrome (MDS)—a blood disorder and precursor to leukemia.

Could sleeping stem cells hold key to treatment of aggressive blood cancer?

July 29, 2013
Scientists studying an aggressive form of leukaemia have discovered that rather than displacing healthy stem cells in the bone marrow as previously believed, the cancer is putting them to sleep to prevent them forming new ...

Drug offers promising approach to improve outcome for children with high-risk leukemia

November 15, 2013
Combining the drug gemtuzumab ozogamicin (GO) with conventional chemotherapy may improve the outcome of bone marrow transplantation for some children battling high-risk acute myeloid leukemia (AML), according to a study led ...

Recommended for you

New therapeutic approach for difficult-to-treat subtype of ovarian cancer identified

July 24, 2017
A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Anti-cancer chemotherapeutic agent inhibits glioblastoma growth and radiation resistance

July 24, 2017
Glioblastoma is a primary brain tumor with dismal survival rates, even after treatment with surgery, chemotherapy and radiation. A small subpopulation of tumor cells—glioma stem cells—is responsible for glioblastoma's ...

Immune cells the missing ingredient in new bladder cancer treatment

July 24, 2017
New research offers a possible explanation for why a new type of cancer treatment hasn't been working as expected against bladder cancer.

No dye: Cancer patients' gray hair darkened on immune drugs

July 21, 2017
Cancer patients' gray hair unexpectedly turned youthfully dark while taking novel drugs, and it has doctors scratching their heads.

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.