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Tracing the Cause of Leukemia in Gene Therapy Trial

By Nancy Touchette

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Leukemia and Lymphoma

Leukemia cells from gene therapy patient.
Last year, researchers in France halted a gene therapy trial because two young patients developed leukemia. The patients suffered from a rare genetic disorder caused by a missing immune system gene. In October, researchers determined that the delivery of the missing gene was somehow activating a known cancer-causing gene in the patients’ genomes.

Now a new study in mice offers an explanation of what went wrong. Researchers from the National Cancer Institute in Frederick, Maryland, report in Science that the gene delivered to the patients is itself a possible cancer-causing gene.

The high incidence of leukemia perplexed researchers. Ninety-nine percent of the genome doesn’t code for any genes at all. The likelihood of the missing gene getting inserted within or near any gene, much less a cancer-causing gene, was thought to be extremely rare. But out of 10 patients enrolled in the trial, two had the same insertion in the same gene and both developed leukemia.

The patients were being treated for severe combined immune deficiency, also known as the bubble baby disease because patients have such compromised immune systems that they must live in isolated environments. The patients were missing a gene called IL2RG.

Replacing the gene effectively cured the immune disease, but caused leukemia in the two patients. These patients have been treated with chemotherapy and are in now in remission. No other patients have developed leukemia.

Most studies show that in order for any cancer to develop, several cancer-causing genes must be disrupted within the same cell. Inserting one cancer-causing gene into another cancer-causing gene increases the chances that leukemia could develop, according to Neal Copeland who led the recent study.

“Cancer doesn’t result from one mutation,” says Copeland. “But our data suggest that putting a cancer gene in a virus causes it to be overactive. By itself, it’s not enough to cause cancer. But if it happens to land near another cancer-causing gene then you get cancer.”

Copeland has developed a database that contains a long list of potential cancer-causing genes in mice. He has found two tumors in mice with insertions in IL2RG, the gene replaced in the gene therapy trial. He also found two tumors with insertions in the same gene that became activated in the leukemia patients. And he found one tumor with insertions in both genes.

In the trial, the replacement gene was overactive and not regulated the same way it is in a normal cell. As a result, says Copeland, cells expressing the replacement gene could grow better than those without the gene.

In a few rare cells, the replacement gene ended up near another cancer-causing gene, and cells could grow even faster. It’s likely that these fast-growing cells rapidly replaced healthy cells in the patients’ blood, causing leukemia.

“Before conducting any further gene therapy trials it might be wise to first check our database and see if the gene of interest is a potential cancer-causing gene,” says Copeland. “If the gene is listed in our database, it might not be a wise choice for gene therapy.”

Davé, U.P. et al. Gene therapy insertional mutagenesis insights. Science 303 333 (January 16, 2004).
Hacein-Bey-Abina et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302 415-419 (October 17, 2003).

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