Somehow, for reasons no one knows, two pieces of genetic code within a cell can swap places. It happens with no signs and no warning. But when that abnormal cell survives and multiplies, life may never be the same for the person carrying it.
City of Hope’s Ya-Huei Kuo, Ph.D., assistant professor in the Division of Stem Cell and Leukemia Research, studies one such rearrangement, which is called chromosome 16 inversion. The rearrangement appears to underlie a form of acute myeloid leukemia (AML), one of the most common types of leukemia in adults.
 Ya-Huei Kuo pursues leukemia stem cells’ secrets. (Photo by p.cunningham) |
Her investigations are so promising they recently earned her a two-year, $200,000 V Scholar Award from The V Foundation for Cancer Research.
“Chromosome 16 inversion is one of the most frequent chromosome rearrangements found in a subset of acute myeloid leukemia patients,” Kuo explained. Understanding the molecular mechanisms underlying its function eventually may lead to more targeted therapies not only for AML, but for other cancers, as well.
Last year, doctors diagnosed nearly 13,000 new cases of AML in the U.S. Despite improvements in survival rates for leukemia patients during the past 50 years, fewer than 23 percent of AML patients survive five years after diagnosis, according to the National Cancer Institute.
Researchers believe part of the reason AML is so difficult to fight is because of leukemia stem cells. These are the quiet “seed” cells that give rise to the disease and make it virtually impossible to destroy conventionally. Today, most cancer treatments only attack rapidly proliferating cells, not these dormant cells that resist therapy, eventually awaken and cause a relapse.
Kuo suspects that altered gene expression may be crucial to these stem cells and a key reason why the disease arises and is so difficult to cure. The cancer-driving pathways may also protect the leukemia stem cells, she said.
She began investigating the phenomenon as a postdoctoral fellow when she generated what she describes as a “conditional knock-in mouse” to mimic the chromosome 16 inversion mutation in normal hematopoietic stem cells (stem cells of the blood and bone marrow).
According to her studies, the inversion of chromosome 16 results in an abnormal fusion protein that impairs cells’ differentiation or maturation. This is a crucial aspect to cancer because these abnormal, immature stem cells cannot produce normal blood cells and are susceptible to transformation into leukemia.
The V Foundation grant will help her learn far more about how leukemia stem cells work.
“The first component of this grant is to characterize this leukemia stem cell population, such as what kind of surface markers it has, and its growth properties,” said Kuo. “Then we can search for the gene expression signatures of these leukemia stem cells, and look for certain pathways that are misregulated as compared to those in normal stem cells.”
She suspects that the fusion protein interacts with other regulatory proteins in the leukemia stem cell to keep these stem cells from maturing properly.
“We’re asking this question: ‘Is the function of the fusion protein crucial to leukemia stem cells?’” she said. “If so, how can we effectively block its function? The other component of this grant is to systemically identify interacting proteins important for the fusion protein’s leukemogenic [leukemia-developing] function. This will give us an array of target options to further develop directed therapy.”
Kuo sees exciting times ahead as scientists build knowledge about leukemia stem cells and explore strategies to attack or manipulate them.
Said Kuo: “My laboratory is now poised to explore the mechanism of disease maintenance and the therapeutic potential of targeting leukemia stem cells, the cell population fueling propagation of leukemia.”