MLL happens when a piece of chromosome 11 breaks off at the normal MLL-associated gene. The broken gene attaches itself to another chromosome, resulting in a fusion protein that eventually causes uncontrolled growth of blood cells.
The lab of senior author Xianxin Hua, MD, PhD, an associate professor of Cancer Biology at the University of Pennsylvania School of Medicine, found that this runaway growth triggered by the fusion protein is blocked when the gene for the normal protein is deleted from leukemia cells. This indicates that the normal protein is required for MLL to proliferate. The findings appear in the current issue of Cancer Cell, and are featured on the cover. Hua is also an associate investigator of the Abramson Family Cancer Research Institute.
The chromosomal breakages and reattachments of MLL, called translocations, are common in many aggressive leukemias. Children with mixed lineage leukemia have a poor treatment outlook because they do not respond well to standard therapies for other types of leukemia, and they often suffer from early relapse after chemotherapy.
MLL translocations come in a variety of types, causing the fusion of the normal gene with one of over 60 other genes on other chromosomes known to work in human leukemias. The fusion protein triggers leukemia, partly through modifying chromatin, a DNA-protein complex.
The researchers also discovered that the normal MLL protein cooperates with the fusion proteins via chemical modifications to chromosomes, which regulate what genes should be turned on or off; by increasing survival of leukemia cells; and by maintaining leukemia stem cells.
"This research not only uncovers the crucial role of a normal protein key to the development of MLL, but also how the cancer cells stay alive in the first place," says Hua. The unraveling of the new, yet little-anticipated, molecular player behind MLL points to the normal MLL gene as a potential target for new therapies, partly through repressing leukemia stem cells.
Building on this discovery, Hua's team will further investigate whether mixed lineage leukemia cells are particularly "addicted" to normal MLL protein, a non-oncogene, in their growth and survival and whether normal MLL proteins specifically cooperate with other factors to sustain leukemia stem cells, with the hope of searching for an Achille's heel of this aggressive leukemia.
Gary Koretzky, MD, PhD, professor of Pathology and Laboratory Medicine at Penn, and Patricia Ernst, Ph.D, assistant professor of Genetics, at Dartmouth College also participated in the research. Other co-authors are Austin T. Thiel, Peter Blessington, Danielle Feather, Xinjiang Wu, Jizhou Yan, Hui Zhang, and Zuguo Liu.
The study was funded partly by a National Institutes of Health (NIH) grant, a Leukemia and Lymphoma Society SCOR grant, and an NIH T32 training grant.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $3.6 billion enterprise.
Penn’s School of Medicine is currently ranked #3 in U.S. News & World Report’s survey of research-oriented medical schools, and is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $367.2 million awarded in the 2008 fiscal year.
Penn Medicine’s patient care facilities include:
The Hospital of the University of Pennsylvania – the nation’s first teaching hospital, recognized as one of the nation’s top 10 hospitals by U.S. News & World Report.
Penn Presbyterian Medical Center – named one of the top 100 hospitals for cardiovascular care by Thomson Reuters for six years.
Pennsylvania Hospital – the nation’s first hospital, founded in 1751, nationally recognized for excellence in orthopaedics, obstetrics & gynecology, and behavioral health.
Additional patient care facilities and services include Penn Medicine at Rittenhouse, a Philadelphia campus offering inpatient rehabilitation and outpatient care in many specialties; as well as a primary care provider network; a faculty practice plan; home care and hospice services; and several multispecialty outpatient facilities across the Philadelphia region.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2009, Penn Medicine provided $733.5 million to benefit our community.
Karen Kreeger | EurekAlert!
Scientists spin artificial silk from whey protein
24.01.2017 | Deutsches Elektronen-Synchrotron DESY
Choreographing the microRNA-target dance
24.01.2017 | UT Southwestern Medical Center
A Swedish-German team of researchers has cleared up a key process for the artificial production of silk. With the help of the intense X-rays from DESY's...
For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.
According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
24.01.2017 | Physics and Astronomy
24.01.2017 | Life Sciences
24.01.2017 | Health and Medicine