Researchers at the Program in Cellular and Molecular Medicine and the Immune Disease Institute at Children's Hospital Boston (PCMM/IDI) have found a link between a common mutation that can lead to cancer and a distant gene regulator that enhances its activity. Discovery of this relationship could lead to drugs targeting B-cell lymphomas, including Burkitt's lymphoma, an aggressive cancer in children, as well as multiple myelomas and other blood-related cancers.
Lymphomas often originate in B cells, the same cells that produce antibodies to help fight infections. A B cell can become cancerous if a gene known as c-myc leaps to another section of DNA (the IgH region, responsible for building antibodies), fuses with it, and somehow becomes over-activated. Scientists have wondered for years how this oncogenic activation occurs, in particular what component in the IgH region activates c-myc. The new study, published in the Dec. 10 issue of Nature, identifies this regulatory component, and marks the first time researchers are able to understand how this movement of genes, or "chromosomal translocation," can hijack a B cell's operation badly enough to lead to cancer.
"IgH-to-myc translocation is the classic example of activation of an oncogene in cancer," says Frederick Alt, PhD, scientific director of PCMM/IDI and senior author of the study. "But nobody really understood how it works."
Aberrant DNA translocations can occur during two different stages of a B cell's development: during a process known as VDJ recombination, when a progenitor B cell creates an antibody to fight a specific pathogen, or during class switch recombination, when a mature B cell gives its antibody a different strategy to fight infection (changing from an IgM to an IgG antibody, for example). Based on their past research , Alt and his colleagues decided to focus on one part of the IgH region called IgH 3' regulatory region (IgH3'RR). They had already shown IgH3'RR to be a far-reaching gene regulator that enhances the transcription of neighboring genes in the IgH region during class switch recombination.
To investigate the relationship between IgH3'RR and lymphoma, the team, led by Alt and first author Monica Gostissa, PhD, of PCMM/IDI, deleted the IgH3'RR in a line of mutant mice previously generated in the Alt lab. These mice routinely develop a B-cell lymphoma in which c-myc is translocated to the IgH region of the DNA. However, without IgH3'RR, mature B cells did not become cancerous, suggesting that mature B cells -- from which most human lymphomas originate -- need IgH3'RR in order to develop into lymphoma.
"The study shows that the IgH3'RR is a key element for turning on the cancer-causing activity of c-myc after it is translocated to the IgH locus," says Alt. He noted that the study also shows that the cancer-causing activity of the IgH3'RR on c-myc can extend over surprisingly long chromosomal distances.
The study suggests the IgH3'RR as a new target for arresting lymphomas and other blood-related cancers that arise from mature B cells. Though inactivating IgH3'RR can impair a B cell's versatility in creating different classes of antibodies, it would not leave a patient immune-deficient because the B cells would retain some of their activity, says Gostissa. Furthermore, such a treatment would be reversible.
The next step is for the researchers to see what eliminating IgH3'RR will do to existing tumors, and then to create a cell-based drug screening assay to test for possible IgH3'RR inhibitors.
The study was funded by grants from the National Institutes of Health and the Leukemia and Lymphoma Society of America (including funds from the de Villiers International Achievement Award). Alt is an investigator of the Howard Hughes Medical Institute.Monica Gostissa, Catherine T. Yan, Julia M. Bianco, Michel Cogne, Eric Pinaud and Frederick W. Alt. "Long-range Oncogenic Activation of IgH/c-myc Translocations by the IgH 3' Regulatory Region."
Nature. Dec. 10, 2009.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 13 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School.
Rob Graham | EurekAlert!
Minimising risks of transplants
22.02.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
FAU researchers demonstrate that an oxygen sensor in the body reduces inflammation
22.02.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg
Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
22.02.2018 | Life Sciences
22.02.2018 | Physics and Astronomy
22.02.2018 | Earth Sciences