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.
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.
Christopher Rucas | EurekAlert!
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy