Study involving twin sisters provides clues for battling aggressive cancers

PUBLIC RELEASE DATE:

9-Feb-2014

Contact: Nick Miller nicholas.miller@cchmc.org 513-803-6035 Cincinnati Children's Hospital Medical Center

CINCINNATI Analyzing the genomes of twin 3-year-old sisters one healthy and one with aggressive leukemia led an international team of researchers to identify a novel molecular target that could become a way to treat recurring and deadly malignancies.

Scientists in China and the United States report their findings online Feb. 9 in Nature Genetics. The study points to a molecular pathway involving a gene called SETD2, which can mutate in blood cells during a critical step as DNA is being transcribed and replicated.

The findings stem from the uniquely rare opportunity to compare the whole genomes of the monozygotic twin sisters (which means they came from a single egg). This led to a series of follow up experiments in human samples from leukemia patients and mouse models of human disease. Those tests verified and extended initial findings researchers gleaned from the twin sisters' blood samples, according to Gang Huang, PhD, co-corresponding author and a researcher in the divisions of Pathology and Experimental Hematology and Cancer Biology at Cincinnati Children's Hospital Medical Center.

"We reasoned that monozygotic twins discordant for human leukemia would have identical inherited genetic backgrounds and well-matched tissue-specific events," Huang said. "This provided a strong basis for comparison and analysis. We identified a gene mutation involving SETD2 that contributes to the initiation and progression of leukemia by promoting the self-renewal potential of leukemia stem cells."

The twin sisters' genomes were compared at the laboratory of co-corresponding author Qian-fei Wang, PhD, Beijing Institute of Genomics, Chinese Academy of Sciences in Beijing, China. The sick sister had a particularly acute and aggressive form of the acute myeloid leukemia (AML) known as MLL, or multi-lineage leukemia.

Acute and aggressive leukemia like MLL develops and progresses rapidly in patients, requiring prompt treatment with chemotherapy, radiation or bone marrow transplant. These treatments can be risky or only partially effective. About 70 percent of people with AML respond initially to standard chemotherapy. Unfortunately, five-year survival rates vary between 15-70 percent, depending on the subtype of AML.

The researchers including co-corresponding author Tao Cheng, MD, Chinese Academy of Medical Sciences & Peking Union Medical College in Tianjin, China are searching for improved and more targeted treatment strategies. The authors show in their current study that the onset of aggressive and acute leukemia is fueled by a spiraling cascade of multiple gene mutations and what are called chromosomal translocations essentially incorrect alignments of DNA and genetic information during cell replication.

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Study involving twin sisters provides clues for battling aggressive cancers