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Genome-wide mouse study yields link to human leukemia

Thanks to a handful of very special mice, scientists have discovered a new tumor suppressor gene and a unique chemical signature implicated in the development of human leukemia, findings that open up a treasure box of opportunity and possibility, study authors say.

Researchers in The Ohio State University Comprehensive Cancer Center bred a type of mouse that develops acute lymphoblastic leukemia (ALL). The mouse first goes through a pre-leukemic stage marked by rapidly expanding T cells and natural killer cells, both major components of the immune system.

In comparing the mice in the pre-leukemic stage and those with ALL with normal mice, researchers found that methylation, a chemical process that adds methyl molecules to DNA, silenced a number of genes but only in the mice with full-blown ALL. Further tests revealed that the methylation pattern in the mice with leukemia is strikingly similar to the pattern of methylation in human leukemia.

In the process, the researchers also identified a new gene that when methylated, appears to interrupt normal cell death, a process called apoptosis. Its given us a whole new way to look at and possibly treat leukemia, says Michael Caligiuri, director of the OSU Comprehensive Cancer Center (OSUCCC) and senior co-author of the study. Its also validated our mouse model as a good predictor of what happens in the development of human disease, he added.

The findings appear in Nature Genetics online at http://www.nature.com/ng/.

This is the first time anyone has examined methylation in leukemia on a genome-wide basis in a mouse, and the findings offer important implications for patient care, since we know that methylation, which alters gene function, can be reversed, says Christoph Plass, senior co-author and a member of the OSUCCCs Molecular Biology and Cancer Genetics and Experimental Therapeutics Programs.

While it was Caligiuris laboratory that designed the mouse model, it was Plass who supervised the methylation studies. He and his colleagues used a system called Restriction Landmark Genome Sequencing (RLGS) to compare methylation patterns among the three groups of mice a method of using enzymes and gel electrophoresis to map tiny bits of DNA on a grid. The stretches of DNA, referred to as fragments, show up as smudgy blobs on a test film. If a fragment is dark and definite, it is not methylated. If, on the other hand, it loses at least 30 percent of its intensity, it is regarded as methylated.

In the study, the research team tested 2447 fragments in each animal. They found anywhere from 45 to 209 (.8 percent to 8.5 percent) of the fragments methylated in the mice with cancer, but only one or two methylated fragments in the other mice. Interestingly, that same range of methylated fragments is exactly what we find in human leukemia, too, says Caligiuri, so that gives added merit to our mouse model as an investigative tool. Using data from the methylation studies, Caligiuri and Plass were able to identify a particular stretch of DNA, called Id4, as a tumor suppressor gene.

Tumor suppressor genes help control cancer by identifying and getting rid of defective cells before they have a chance to mature and divide. When tumor suppressor genes lose that ability as they can if they are silenced through methylation or some other process, it gives cancer a chance to establish a foothold and spread.

Caligiuri says much more work needs to be done, but adds that the identification of Id4 as a likely tumor suppressor gene gives clinicians another possible target for intervention. We already have a drug, decitabine, that we know can reverse the effects of methylation, says Plass. We are just beginning to figure out how it best works in humans, but simply knowing that we have a new target that may be meaningful in treating leukemia is a big step in the right direction.

Grants from the National Cancer Institute and the Leukemia and Lymphoma Society supported the research.

Additional co-authors from Ohio State include Li Yu, Chunhui Liu, Jeff Vandeusen, Brian Becknell, Zunyun Dai, Yue-Zhong Wu, Aparna Raval, Te-Hui Liu, Wei Ding, Charlene Mao, Shujun Liu, Laura Smith, Stephen Lee, Guido Marcucci and John Byrd. Laura Rassenti, from the University of California , San Diego , also contributed to the project.

The Ohio State University Comprehensive Cancer Center is a network of interdisciplinary research programs with over 200 investigators in 13 colleges across the OSU campus, the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and Childrens Hospital, in Columbus . OSUCCC members conduct research on the prevention, detection, diagnosis and treatment of cancer, generating over $95 million annually in external funding.

Girl's marrow will benefit baby sister

By Dorothy Yagodich
FOR THE TRIBUNE-REVIEW

June 19, 2005 - Justess Pletcher is a smiling little girl, a picture of health. Yet inside this 19-month-old lurks myelodysplastic syndrome, or MDS, a rare type of blood disorder or leukemia normally found in people 50 years or older. When Jody Pletcher took her daughter for the 18-month booster shot, Justess ran a fever with an eye infection. Pletcher was told the infection was viral and antibiotics would not help.

"When they took a blood sample, they told us to get to Children's Hospital in Pittsburgh immediately," Jody Pletcher said. The little girl spent the next nine days in the hospital.

"We were told Justess is the youngest MDS case Children's Hospital has ever seen," said Larry Pletcher, Justess' father.

Since May 11, Justess has had 10 hemoglobin and platelet transfusions. That did help boost her platelet count.

Justess is undergoing experimental chemotherapy on Mondays, Wednesdays and Fridays. "We are in the second week of the three-week series," said Larry Pletcher. Her last treatment was Friday and a bone marrow transplant is scheduled for today.

The Belle Vernon couple was fortunate to find their 7-year-old daughter, Journie, is a sibling match. The rejection rate is about 1 percent between siblings, he said.

"Journie is 7 going on 30. She said she would do anything in her power to save her sister," Larry Pletcher said. "It's a 50-50 shot."

"Journie said, 'God put me here to help save my sister,'" said her mother. Journie is a first-grade student at St. Sebastian School in Belle Vernon.

The bone marrow transplant is something that has to happen, said Jody Pletcher. Of the "X" chromosomes, one "X" of the seven is missing, she explained.

Personnel at Children's Hospital have been fantastic, Larry Pletcher said, adding that Dr. L. Krishnamurti "tells us everything. This doctor goes into detail to explain what is happening. The hospital is out of this world, just wonderful."

Hospital personnel have given Justess a toy stethoscope, since the real version often frightened her. They have talked with Journie to explain what is happening in ways to help a child understand.

For now the family is on a hectic, expensive schedule -- three days a week in Pittsburgh, with food and travel costs. Larry Pletcher, who works for the Schwanns Food Company, has taken a family emergency medical leave. His wife is a stay-at-home mom. Although they have some health insurance, they have not even begun to calculate the costs involved.

"This has been like a slap in the face," Jody Pletcher said. "As parents, it's overwhelming. We just go one day at a time."

MDS has presented the most devastating challenge to the couple in their nine-year marriage.

A former Belle Vernon resident, Larry Pletcher was in the military, serving at the Minot Air Base in North Dakota. Jody lived close by in the small town of Lansford, when they met and fell in love. They chose to name their daughters Journie and Justess, "since we both like seven-letter J-names."

"Justess often kisses the Miraculous Medal," said her father, pointing to the religious medal on a slim gold chain circling the little girl's neck, a gift from Al Stancato, of Belle Vernon.

Stancato befriended the couple when he heard about their plight. When his 8-month-old son was diagnosed with medical anemia, Stancato later became a volunteer for the Leukemia Society. He has raised $80,000 since 1996 through walk-a-thons and such activities to help with medical research. "My son is now 43 and healthy," Stancato added.

The Pletchers want Justess to be healthy, too. "We know we are at the best place at Children's Hospital. We are hopeful," Larry Pletcher added.

Anyone who would like to help the Pletchers with medical expenses can contribute to the Justess Pletcher Fund at National City Bank at 433 Broad Ave., Belle Vernon, PA 15012.

A Justess Pletcher Fund for family expenses has also been established at the Belle Vernon Credit Union, 608 Rostraver Road, Belle Vernon, PA 15012.

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