(Press-News.org) Scientists have discovered the survival secret to a genetic mutation that stokes leukemia cells, solving an evolutionary riddle and paving the way to a highly targeted therapy for leukemia. In a paper published today in Cell, researchers at NYU Langone Medical Center describe how a mutated protein, called Fbxw7, behaves differently when expressed in cancer cells versus healthy cells. "Fbxw7 is essential for making blood cells, so the big mystery is why a mutation on a gene so important for survival would persist," says lead author Iannis Aifantis, PhD, chair of pathology at NYU Langone Medical Center and an Early Career Scientist at Howard Hughes Medical Institute. "What we've found is that the mutation affects cancerous cells but not healthy cells."
The Fbxw7 protein regulates the production of so-called hematopoietic stem cells, precursors that give rise to all types of blood cells. Without Fbxw7, the body loses the ability to produce blood and eventually succumbs to anemia. Scientists are only beginning to understand why mutated Fbxw7 appears in a significant portion of human tumors, including gastric, prostate, and some breast cancers. The mutation is especially prevalent in T-cell acute lymphoblastic leukemia, or T-ALL, a rare but lethal type of pediatric leukemia that causes the over-production of immature white blood cells.
In their experiments, Dr. Aifantis, working in collaboration with graduate student Bryan King and others, began by introducing mutated Fbxw7 into healthy blood stem cells in mice. "We thought the mutation would induce anemia, just as it does when Fbxw7 is deleted," says Dr. Aifantis. But to the researchers' surprise, nothing happened—the stem cells continued to manufacture blood cells.
When the researchers then introduced in mice the mutated Fbxw7 into leukemic blood stem cells—those that overproduce white blood cells and cause leukemia—the cancer accelerated. "We found that the mutation made leukemia stem cells much more aggressive," Dr. Aifantis says.
In follow-up experiments, the researchers showed that Fbxw7 binds to and degrades a protein called Myc, which fuels leukemic stem cells, and has long been associated with many other cancers and the recurrence of cancer after treatment. When Fbxw7 is mutated, Myc is left unchecked, they found, and the population of cancer stem cells swells. This insight also helps explain why healthy blood stem cells seem to "ignore" mutated Fbxw7. Unlike leukemic stem cells, healthy blood stem cells typically lie dormant until the body requires an emergency supply of blood and they rarely express Myc. "Normal blood stem cells express very little Myc because they are not cycling. A mutation does not affect the substrate because the substrate does not exist," says Dr. Aifantis. "Leukemia stem cells, however, do express Myc and Fbxw7 mutations increase its abundance."
The researchers then wondered if eliminating Myc could potentially block leukemia. Indeed, deleting the Myc gene in mice with leukemia depleted leukemic stem cells and stopped the growth of tumors. They achieved the same results in mice and human cell and bone marrow samples of T-ALL using a new class of cancer drug called a BET inhibitor that blocks Myc. "We found that the BET inhibitor could actually kill leukemia stem cells. And without stem cells, the leukemia simply cannot grow," says Dr. Aifantis.
The researchers believe they can use the BET inhibitor to target pediatric and adult T-ALL leukemia. This work was supported by a grant from the National Cancer Institute.
INFORMATION:
About NYU Langone Medical Center
NYU Langone Medical Center, a world-class, patient-centered, integrated, academic medical center, is one of the nation's premier centers for excellence in clinical care, biomedical research and medical education. Located in the heart of Manhattan, NYU Langone is composed of four hospitals – Tisch Hospital, its flagship acute care facility; the Hospital for Joint Diseases, recognized as one of the nation's leading hospitals dedicated to orthopaedics and rheumatology; Hassenfeld Pediatric Center, a comprehensive pediatric hospital supporting a full array of children's health services; and Rusk Rehabilitation, inpatient and outpatient therapy services devoted entirely to rehabilitation medicine – plus NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The medical center's tri-fold mission to serve, teach and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education and research. For more information, go to http://www.NYULMC.org.
END
San Francisco, CA. (June 20, 2013) – Residents in anesthesiology training programs have high rates of burnout and depression, reports a survey study in the July issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).
The findings raise concerns that, "In addition to effects on the health of anesthesiology trainees, burnout and depression may also affect patient care and safety," write Dr Gildasio S. de Oliveira, Jr, and colleagues of Northwestern University, Chicago.
Burnout and Depression Are Common in Anesthesia Trainees…
The ...
San Francisco, CA. (June 20, 2013) – Retention of guidewires used to place central venous catheters (CVCs) is a complication that is considered always preventable—but nevertheless still happens, according to a report in the July issue of Anesthesia & Analgesia, official journal of the International Anesthesia Research Society (IARS).
Dr Andrea Vannucci and colleagues report their hospital's experience of four patients with retained guidewires, and analyze risk factors for these rare, preventable medical errors. A pair of accompanying editorials support the need for more ...
WASHINGTON —More than three-quarters (81.8 percent) of unscheduled admissions to the hospital now come through the emergency department, which is a sharp increase from the previous decade when only 64.5 percent of unscheduled admissions came through the ER. A study, published early online this week in the journal Medical Care, re-confirms recent findings by the RAND Corporation highlighting the growing role emergency physicians play in health care beyond the emergency department ("Changes in the Source of Unscheduled Hospitalizations in the United States").
"Although ...
VIDEO:
This time-lapse movie shows a solar eruption that happened on June 7, 2011. At lower right, material blasts outward from the sun and then splashes down again, creating dramatic flashes...
Click here for more information.
On June 7, 2011, our Sun erupted, blasting tons of hot plasma into space. Some of that plasma splashed back down onto the Sun's surface, sparking bright flashes of ultraviolet light. This dramatic event may provide new insights into how young stars ...
Since the discovery of the Van Allen radiation belts in in the Earth's upper atmosphere in 1958, space scientists have believed that these belts consisted of two doughnut-shaped rings of highly charged particles — an inner ring of high-energy electrons and energetic positive ions, and an outer ring of high-energy electrons.
However, in February of this year, a team of scientists reported in the journal Science the surprising discovery of a previously unknown third radiation ring. This narrow ring had briefly circled the Earth between the inner and outer rings in September ...
A team of researchers from Texas and Colorado has identified a variety of factors that influence the likelihood of E. coli contamination of spinach on farms prior to harvest. Their research is published in the July 2013 issue of the journal Applied and Environmental Microbiology.
"Microbial contamination of produce seems strongly influenced by the time since the last irrigation, the workers' personal hygiene and the field's use prior to planting of produce," says first author Sangshin Park of Texas A&M University, College Station. "These factors, together with the role ...
"Enhancing student engagement has been identified as the key to addressing problems of low achievement, high levels of student misbehavior, alienation, and high dropout rates." – Pitt professor Ming-Te Wang
PITTSBURGH—A student who shows up on time for school and listens respectfully in class might appear fully engaged to outside observers, including teachers. But other measures of student engagement, including the student's emotional and cognitive involvement with the course material, may tell a different story—one that could help teachers recognize students who are ...
Bacterial DNA may integrate into the human genome more readily in tumors than in normal human tissue, according to a new study from the University of Maryland School of Medicine's Institute for Genome Sciences. Researchers analyzed genomic sequencing data available from the Human Genome Project, the 1,000 Genomes Project and The Cancer Genome Atlas (TCGA). They considered the phenomenon of lateral gene transfer (LGT), the transmission of genetic material between organisms in the absence of sex.
Scientists have already shown that bacteria can transfer DNA to the genome ...
DURHAM, N.C. -- Duke University biomedical engineers and genome researchers have developed a proof-of-principle approach using light to detect infections before patients show symptoms.
The approach was demonstrated in human samples, and researchers are now developing the technique for placement on a chip, which could provide fast, simple and reliable information about a patient. A diagnostic device based on this chip also could be made portable.
The researchers developed a silver-based nanoparticle that homes in on a specific molecular marker that spills into the bloodstream ...
No matter how we jump, roll, sit, or lie down, our brain manages to maintain a visual representation of the world that stays upright relative to the pull of gravity. But a new study of rider experiences on the Hong Kong Peak Tram, a popular tourist attraction, shows that specific features of the environment can dominate our perception of verticality, making skyscrapers appear to fall.
The study is published in Psychological Science, a journal of the Association for Psychological Science.
The Hong Kong Peak Tram to Victoria Peak is a popular way to survey the Hong Kong ...
