University of Chicago Medicine
Comprehensive Cancer Center (UCCCC) scientists have discovered the tumor
suppressor gene involved in acute myeloid leukemia.
In 1973, Janet Rowley, PhD,
Blum-Riese Distinguished Service Professor of Medicine, Molecular Genetics and
Cell Biology, and Human Genetics, was examining the DNA of leukemia cells and
observed that one copy of chromosome 7 was missing. She deduced that one out of
the more than 1,000 genes found on chromosome 7 could possibly be responsible
for keeping the growth of leukemia cells in check.
The search for a tumor suppressor
gene continued among Dr. Rowley's colleagues at the University of Chicago. In
the 1990s, Michelle M. Le Beau, PhD, UCCCC director and the Arthur and Marian
Edelstein Professor of Medicine, used a high-resolution technique called
fluorescence in situ hybridization (FISH) to define the segment of chromosome 7
that was commonly deleted. She narrowed the region of interest to about 50
Most recently, in 2009, Kevin
White, PhD, professor of human genetics and director of the Institute for
Genomics and Systems Biology (IGSB), and his research team harnessed advanced
technology to further map the genes. Specifically, they used single nucleotide
polymorphism (SNP) arrays to detect variations in the genes, as well as
next-generation sequencing to analyze gene expression at high sensitivity.
Because these techniques generate
an overwhelming amount of information, Dr. White teamed with IGSB Director of
Informatics Robert Grossman, PhD, to develop a large computing infrastructure
that could meet the processing and storage demands of the biological data being
The analyses indicated that the
CUX1 gene was the most significantly differentially expressed gene in cells
that had lost chromosome 7. Interestingly, the researchers also identified a
CUX1 fusion transcript, in other words, part of CUX1 fused to another gene.
They hypothesized that this disruption in CUX1 may contribute to the growth of
abnormal blood cells, a hallmark of AML.
Next, the researchers tested the
gene's activity in the fruit fly. When they knocked out the CUX1 gene, some of
the fruit flies developed leukemia. Collaborating with John Cunningham, MD,
professor of pediatrics, the investigators carried out similar studies in mice
and again observed that deficient levels of CUX1 contributed to abnormal growth
of blood cells. They described their findings in an article published in the
February 7 issue of Blood, the American Society of Hematology's journal.
The first author of the paper,
Megan McNerney, MD, PhD, instructor of pathology and fellow in Dr. White's
laboratory, said, "This is a uniquely University of Chicago story, starting
with findings from Janet Rowley and continuing over the years with an excellent
group of clinicians and scientists using different technologies who worked
collaboratively on myeloid leukemias." She added that further studies that
reveal how CUX1 regulates other genes will help find a potential pathway that
can be targeted with drugs.
This study was supported by the Cancer Research
Foundation, the Leukemia & Lymphoma Society, the Chicago 1000 Cancer
Genomes Project, and grants CA150631 and CA40046 from the National Cancer
Institute of the National Institutes of Health.