Caligiuri gene

NEW GENE ALTERATION FIND POINTS TO AGGRESSIVE LEUKEMIA TREATMENT

COLUMBUS, Ohio -- Researchers looking at a group of leukemia patients have found that a genetic defect they discovered two years ago serves as an early warning signal, calling for a speed-up in these patients’ treatment.

The defect is a duplication of a small part of the ALL1 gene. Patients who have this alteration fall out of remission three times faster than those who don’t and their survival is slightly more than half that of patients who don’t have the defect.

The scientists reported their discovery in the journal Cancer Research.

The gene defect appears in patients suffering from acute myeloid leukemia (AML), a cancer that afflicts about one in 100,000 people. The disease increases as the population ages and the prognosis of patients with the disease worsens with age. Perhaps 40 percent of those with AML can be cured using appropriate therapies. Without treatment, AML can kill in a few months.

“This is one of only a few instances where we’ve cloned a gene and then figured out what it means in terms of an individual patient’s disease. What’s more, this gene defect is a sign of a poor prognosis. Finding it allows us to better plan a patient’s treatment,” explained Michael Caligiuri, co-director of the division of hematology and oncology and associate director for clinical cancer research for Ohio State University’s Comprehensive Cancer Center. The study was led by Caligiuri and Dr. Clara Bloomfield, director of the CCC and of the division of hematology and oncology.

In approximately 55 percent of the cases of AML, the patient’s chromosomes show distinctive changes that can be linked to the disease. In the remaining 45 percent however, the patients show normal cytogenetics -- that is, there are no obvious chromosomal changes.

This particular defect appears in patients who have normal cytogenetics, Caligiuri said. That is, a typical inspection of the patient’s chromosomes shows none of the chromosomal changes that signal the cause of AML.

Caligiuri and his colleagues examined 98 patients diagnosed with AML but who had normal chromosomes. In 11 of these patients, a closer examination showed that a short segment of the ALL1 gene had been duplicated and spliced back into the gene. In every case with these patients, their prognosis was more serious than that of patients lacking this defect.

Patients with the defect remained in remission from the disease just over seven months while those without the defect maintained remission for nearly two years. The survival time for patients in the study who had the defect was just under 14 months while patients without the defect had an average survival of 20 months.

“This means that about 5 percent of patients with AML have this defect and need to be treated quickly and aggressively,” Caligiuri said, adding that patients with the defect probably should undergo an allogenic bone marrow transplant while in their first remission of the disease if that option is a possibility.

The researchers are now beginning a larger, more comprehensive prospective study intended to validate their retrospective study. Next, they will test the effectiveness of aggressive therapy in patients with the ALL1 defect. Caligiuri suggests that a screening test for the defect, now available at Ohio State, should be widely available this year.

The international collaboration was funded by the Leukemia Society of America, the Lady Tata Memorial Fund, the Cancer Society of Finland and the Coleman Leukemia Research Fund.

Contact: Michael Caligiuri, (614) 293-7521; Caligiuri-1@medctr.osu.edu

Written by Earle Holland, (614) 292-8384; Holland.8@osu.edu