Many things go wrong in cells during the development of cancer. In the middle of the chaos are often genetic switches that control the availability of new cells. In a particularly aggressive form of leukemia, known as acute myeloid leukemia, a genetic switch that manages the maturation of blood stem cells into reddish colored and white blood cells goes awry. Normally, this particular switch leads to appropriate numbers of white and red blood cells. Yet patients with acute myeloid leukemia end up with a dangerous build up of blood stem cells and a lack of red plus white blood cells — cells that are needed to give you the body with oxygen and fight infections.
Now, researchers at Caltech and the Sylvester Comprehensive Cancer Center at the University of Miami are usually narrowing in on a protein that helps control this hereditary switch. In healthy individuals, the protein, called DPF2, stops the production of red and white blood tissue when they do not need to be replaced. That is, it turns the turn off. But the protein can be overproduced in acute myeloid leukemia patients. The protein basically sits on the switch, stopping it from turning back on to make the blood cellular material as needed. Patients who overproduce DPF2 have an especially poor prognosis.
In a new study, to become published the week of May 22, 2017, within the journal Proceedings of the National Academy associated with Sciences , the researchers demonstrate new ways to slow down DPF2, potentially rendering acute myeloid leukemia more curable. They report new structural and functional details about the fragment of DPF2. This new information reveals goals for the development of drugs that would block the protein’s perform.
“Many human diseases, including cancers, occur because of malfunctioning genetic switches, ” says André Hoelz, the corresponding author of the study. Hoelz is a teacher of chemistry at Caltech, a Heritage Medical Study Institute (HMRI) Investigator, and a Howard Hughes Medical Start (HHMI) Faculty Scholar. “Elucidating how they work at atomic details allows us to begin the process of custom tailoring drugs to deactivate them and in many cases that is a significant step towards a cure. inch
Red and white blood cells are usually constantly regenerated from blood stem cells, which live in our bone marrow. Like other stem cells, bloodstream stem cells can live forever. It is only when they will become differentiated into specific cell types, such as reddish colored and white blood cells, that they then become human, or acquire the ability to die after a certain period of time.
“Our bodies use a complex series of genetic buttons to differentiate a blood stem cell into a variety of cell types. These differentiated cells then circulate within the blood and serve a variety of different functions. When these types of cells reach the end of their lifespan they need to be replaced, inch says Hoelz. “This is somewhat like replacing utilized tires on a car. ”
To investigate the particular role of DPF2 and learn more about how it regulates the genetic switch for making blood cells, the Hoelz group partnered with Stephen D. Nimer, co-corresponding writer of the paper and director of the Sylvester Comprehensive Malignancy Center, and his team. First, Ferdinand Huber and Toby Davenport — both graduate students at Caltech within the Hoelz group and co-first-authors of the new study — obtained crystals of a portion of the DPF2 protein that contains a domain known as a PHD finger, which stands for world homeodomain. They then used X-ray crystallography, a process that involves revealing protein crystals to high-energy X-rays, to solve the construction of the PHD finger domain. The technique was carried out at the Stanford Synchrotron Radiation Lightsource, using a dedicated beamline of Caltech’s Molecular Observatory.
The results exposed how DPF2 binds to a DNA-protein complex, called the nucleosome, to block the production of red and white bloodstream cells. The protein “reads” various signals displayed at the nucleosome surface by adopting a shape that suits various modifications on the nucleosome complex, like the different formed pieces of a jigsaw puzzle. Once the protein binds for this DNA locus, DPF2 turns off the switch that manages blood cell differentiation.
The next step was to find out if DPF2 could be blocked in human blood come cells in the lab. Sarah Greenblatt, a postdoctoral relate in Nimer’s group and co-first author of the research, used the structural information from Hoelz’s group to create a mutated version of the protein. The Nimer group then launched the mutated protein in blood stem cells, plus found that the mutated DPF2 could no longer bind towards the nucleosome. In other words, DPF2 could no longer inactivate the change for making blood cells.
“The mutated DPF2 was unable to bind to specific regions in the genome and could not halt blood stem cell differentiation, inch says Huber. “Whether DPF2 can also be blocked in the malignancy patients themselves remains to be seen. ” The researchers say the structural socket in DPF2, one of the puzzle-piece-like regions discovered in the new study, is a good target for candidate medicines.