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New research shows that defective genes and the individual leukemia cells that carry them are organized in a more complex way than previously thought.
The findings challenge the conventional scientific view that cancer progresses as a linear series of genetic events and that all the cells in a tumor share the same genetic abnormalities and growth properties. A report on this work appeared in a recent edition of the scientific journal Nature.
The results are expected to open the way for discovering how genetic abnormalities transform normal cells into leukemic cells as well as aid understanding of how cells at different stages of that genetic evolution respond to therapy or contribute to relapse. The findings also underscore the importance of developing therapies capable of eradicating the diverse population of cancer cells present in all cancer patients.
Now we need to extend this work to identify genetic changes present at low levels in patients at diagnosis that confer a high risk of treatment failure and relapse,” said Charles Mullighan, MD, PhD, Pathology. He is co-first author of the study with Faiyaz Notta, PhD, Ontario Cancer Institute and the University of Toronto.
In this study, researchers demonstrated that the leukemia cells taken from patients with acute lymphoblastic leukemia (ALL) are composed of multiple families, or subclones, of genetically distinct cancer cells. Investigators discovered that cells that propagate the disease and potentially survive therapy persist through generations, sometimes acquiring additional genetic alterations and branching off to form genetically distinct cancer subclones. Some of these genetic families dominate, which sometimes makes it appear that the leukemia cells have only one set of genetic abnormalities. Other ALL subclones are extremely rare, explaining why they were not detected using different techniques.
“Overall, the study proved that many leukemias comprise multiple subpopulations of cells with different genetic alterations, and that these genetic alterations may evolve over time,” Mullighan said.
St. Jude Director and CEO Dr. William E. Evans announces that the hospital has been recognized by FORTUNE magazine as one of the “100 Best Companies to Work For.” This is the first year St. Jude has been included in the publication’s annual list (see related article ).
“St. Jude employees rank pride in the hospital’s mission—finding cures, saving children—as one of the top reasons St. Jude is a great place to work,” Evans said. “For our employees, working at St. Jude is much more than a job.”
St. Jude currently has more than 3,600 faculty and staff. Evans says the mission gives them a unique sense of purpose.
“Employees are proud of their work because it has special meaning,” Evans said. “A key to our success is attracting outstanding people and giving them a place to do their best work. We are successful because of our people and the partnership we have with our patients and our donors. Employees embrace the mission and espouse the culture of St. Jude, which is one of compassion, collaboration and innovation.”
The American Association for Cancer Research recently presented St. Jude Oncology Chair Ching-Hon Pui, MD, with the 2011 Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Research.
Pui played a key role in treatment protocols that raised cure rates of acute lymphoblastic leukemia (ALL) from about 70 percent in the early 1980s to an unprecedented 90 percent at St. Jude today. His work has shown that cranial irradiation, once regarded as a standard treatment for ALL, can be omitted altogether, thus sparing patients from devastating side effects and enhancing their quality of life.
“One of Dr. Pui’s great strengths, beyond his unsurpassed wealth of knowledge about treating leukemia, is that he brings together a broad array of scientists and clinical investigators to participate in developing and conducting new ALL treatment protocols,” said Dr. William E. Evans, St. Jude director and CEO. “He is like a great conductor drawing together the best musicians to create something that is extraordinary and far greater than any one person playing alone.”
David Solecki, PhD, Developmental Neurobiology, and his colleagues have identified key components of a signaling pathway that controls the departure of neurons from the brain niche where they form and allows these cells to start migrating to their final destination. Defects in this system affect the architecture of the brain and are associated with epilepsy, mental retardation and perhaps malignant brain tumors.
The findings provide insight into brain development as well as clues about the mechanism at work in other developing tissues and organ systems. The report appeared recently in the journal Science.
“Neurons are born in germinal zones in the brain, and the places they occupy in the mature brain are sometimes quite a distance away. The cells have to physically move to get to that final destination,” Solecki said. “If the process is compromised, the result is a devastating disruption of brain circuitry that specifically targets children.”
The findings may also offer clues about the spread of malignant brain tumors. Solecki said some types of the pediatric brain tumor medulloblastoma share similarities with immature neurons and seemingly fail to depart the cerebellar germinal zone.
In spring 2009, a novel H1N1 influenza virus emerged in Mexico and became a pandemic. Although extremely young children were most likely to become infected, young adults were more likely than either much younger or much older individuals to develop life-threatening complications.
New research led by Jon McCullers, MD, Infectious Diseases, suggests the young adults may have been susceptible to complications because earlier flu infections primed them for a mismatched immune response to the novel virus.
The study focused on the role that sugar molecules known as glycans play in shaping the immune response to flu. As flu viruses circulate, glycans are added to the proteins studding the viral coat. The process, known as glycosylation, may help the virus elude antibodies programmed to destroy it. In the absence of normally protective antibodies, other immune responses mediated by T-cells caused damage to the lungs instead of the virus. A paper on this work appeared in the American Journal of Respiratory and Critical Care Medicine.
If confirmed, the findings raise new questions about how to factor glycosylation into the design of future flu vaccines.
The first genome-wide study to demonstrate an inherited genetic basis for racial and ethnic disparities in cancer survival linked Native American ancestry with an increased risk of relapse in young leukemia patients. The work was done by investigators at St. Jude and the Children’s Oncology Group (COG).
Along with identifying Native American ancestry as a potential new marker of poor treatment outcome, researchers reported evidence that the added risk could be eliminated by administering an extra phase of chemotherapy. The study involved 2,534 children and adolescents battling acute lymphoblastic leukemia (ALL), the most common childhood cancer. The work appeared in the journal Nature Genetics.
The children were all treated in protocols conducted by St. Jude or COG. Although the overall cure rate for childhood ALL now tops 80 percent, and is close to 90 percent at St. Jude, racial and ethnic disparities have persisted. Based on self-declared status, African-American and Hispanic children with the disease have often fared worse than their white and Asian counterparts. This is the first study to use genomics to define ancestry, rather than relying on self-declared racial or ethnic categories.
“To overcome racial disparity you have to understand the reasons behind it,” said the study’s first author, Jun Yang, PhD, of Pharmaceutical Sciences. “While genetic ancestry may not completely explain the racial differences in relapse risk or response to treatment, this study clearly shows for the first time that it is a very important contributing factor.”
The research identified a possible mechanism linking ancestry and relapse. Hispanic patients, who have a high percentage of Native American ancestry, were more likely than other patients to carry a version of the PDE4B gene that was also strongly associated with relapse. The PDE4B variants were also linked with reduced sensitivity to glucocorticoids, medications that play a key role in ALL treatment.
“This is just one example of how ancestry could affect relapse risk,” said the study’s senior author Mary Relling, PharmD, St. Jude Pharmaceutical Sciences chair. “It is likely that many other genes are involved.”
If regulatory T cells are the immune system’s police force, stepping in as needed to control the immune response, work led by St. Jude researchers recently identified a subset of the specialized white blood cells that may serve as the riot squad.
The new cells are called “induced T regulatory population making IL-35” or iTr35 cells. Research from the laboratory of Dario Vignali, PhD, Immunology vice chair, and his colleagues, showed that iTr35 cells are created from more common less-specialized immune cells known as conventional T cells. Natural regulatory T cells generate iTr35 cells to help them put the brakes on an immune response.
Investigators also determined that a cytokine called interleukin 35 (IL-35) played a pivotal role in iTr35 creation and activity. Vignali’s laboratory discovered IL-35 in 2007. It is one of a small number of cytokines that suppress rather than stimulate the immune response. The recent study showed that IL-35 could convert activated conventional T cells into powerfully suppressive immune cells that used IL-35 as the main weapon of suppression. The research appeared in the journal Nature Immunology. Vignali is the senior author and Lauren Collison, PhD, a postdoctoral fellow, is the first author.
Like a coach shuffling the starting lineup as the season progresses, a key component of the immune system’s strategy for recognizing virus-infected cells often changes during the course of an illness, St. Jude researchers report. The change might help regulate the immune response.
St. Jude investigators developed a technique to track changes in the gene expression of key regions of two proteins known as the alpha and beta chains. Those proteins make up the unique receptor that covers a T cell’s surface and determines the immune cell’s ability to recognize and target cells infected with viruses or bacteria. Scientists used the approach to show production of the RNA message for the receptor’s alpha chain changed in most T cells as infection with influenza A virus progressed.
“We had never previously been able to ask such detailed questions about the alpha chain in the immune response,” said Immunology Postdoctoral Fellow Pradyot Dash, PhD, lead author of a paper on this topic that appeared in the Journal of Clinical Investigation.
The paper’s senior author, Paul Thomas, PhD, Immunology, said the findings will advance understanding of T cell biology and the receptor’s role in shaping the immune response. Investigators hope the results will include more effective vaccines, new immune therapies and insight into the origin of autoimmune disorders.
Students from Bellevue Middle School, the hospital’s Adopt-a-School partner, recently visited St. Jude to participate in an interactive science fair as part of Research Tech Week. Shelly Jackson (center) and Stacie Woolard, PhD, of Tumor Cell Biology help a student understand the properties of polymers by showing him how to make homemade slime out of laundry detergent, glue and water.