Gene for most common childhood cancer identified

By Michael McCarthy

September 9, 2013

An aberrant gene has been found to cause the most common childhood cancer in the world, pre-B cell acute lymphoblastic leukemia.

stained ALL leukemia bone marrow cells
Stained bone marrow aspirate from a patient with acute lymphoblastic leukemia.

The gene, PAX5, has long been known to be involved in acute lymphoblastic leukemia.  The new study indicates a mutation in the gene alone is sufficient to eventually cause the disease, which affects nearly 3,000 children and teenagers in the United States each year.

The discovery should make it possible to screen for the gene in families with a history of the disease and suggests new strategies for treating the disease, said Dr. Marshall Horwitz, professor of pathology and of medicine at the University of Washington. He is a co-author of the new study.

He was joined in the study by researchers at St. Jude Children’s Research Hospital in Memphis, Tennessee led by Dr. Charles Mullighan; Memorial Sloan-Kettering Cancer Center in New York City led by Dr. Kenneth Offit, and others at the UW. The results were published Sept. 8 in the journal Nature Genetics.

The researchers looked at the genes from two unrelated families that had a high rate of acute lymphoblastic leukemia and identified the same mutation of the PAX5 gene that ran in both the families.

This variant does not cause leukemia as long as it is paired with a normal version of the PAX5 gene, said Horwitz, but if the normal copy of the gene is lost and only the abnormal variant remains, some blood cells fail to become normally functioning white blood cells and, instead, turn into leukemia cells.

In the case of the families in the study, all the children who developed leukemia had damage to a chromosome in the affected blood cells. The damage, in which part of chromosome 9 was lost, removed the normal copy of the PAX5 gene. This left the abnormal gene unopposed.

PAX5 codes for a kind of protein, called a transcription factor, that plays a key role not only in blood cell maturation, but also in embryonic development.

“It was not a surprise that PAX5 turned out to be involved. It’s  the most commonly mutated gene found in ALL cells,” said Horwitz. “But it has not been clear whether PAX5 mutations were just mutations that had to happen at some point in the transformation of a normal cell to a leukemic cell or whether PAX5 variants were driving the leukemia.”

He said the findings indicate that PAX5 variants alone are sufficient to eventually cause acute lymphoblastic leukemia.

The finding has another important implication, said Horwitz. The fact that PAX5 is sufficient to cause acute lymphoblastic leukemia supports the concept that mutations that affect differentiation of blood cells are the key drivers of leukemia. If that is the case, it may be possible to design treatments that block de-differentiation or induce leukemic cells to re-differentiate so that they would begin to behave like normal cells again.

Such treatments might be more effective and have far fewer side effects than chemotherapy, the current standard treatment for these cancers, said Horwitz.