New research shows how a protein controls blood cell production in leukemia.

In healthy individuals, the protein, called DPF2, stops the production of red and white blood cells when they do not need to be replaced. That is, it turns the switch off. But the protein can be overproduced in acute myeloid leukemia patients. The protein basically sits on the switch, preventing it from turning back on to make the blood cells as needed. Patients who overproduce DPF2 have a particularly poor prognosis.

In a new study, to be published the week of May 22, 2017, in the journal Proceedings of the National Academy of Sciences, the researchers demonstrate new ways to impede DPF2, potentially rendering acute myeloid leukemia more treatable. They report new structural and functional details about a fragment of DPF2. This new information reveals targets for the development of drugs that would block the protein's function.

To investigate the role of DPF2 and learn more about how it controls the genetic switch for making blood cells, the Hoelz group partnered with Stephen D. Nimer, co–corresponding author of the paper and director of the Sylvester Comprehensive Cancer Center, and his team. First, Ferdinand Huber and Andrew Davenport – both graduate students at Caltech in the Hoelz group and co–first–authors of the new study – obtained crystals of a portion of the DPF2 protein containing a domain known as a PHD finger, which stands for planet homeodomain. They then used X–ray crystallography, a process that involves exposing protein crystals to high–energy X–rays, to solve the structure of the PHD finger domain. The technique was performed at the Stanford Synchrotron Radiation Lightsource, using a dedicated beamline of Caltech's Molecular Observatory.

The results revealed how DPF2 binds to a DNA–protein complex, called the nucleosome, to block the production of red and white blood cells. The protein "reads" various signals displayed on the nucleosome surface by adopting a shape that fits various modifications on the nucleosome complex, like the different shaped pieces of a jigsaw puzzle. Once the protein binds to this DNA locus, DPF2 turns off the switch that regulates blood cell differentiation.

The next step was to see if DPF2 could be blocked in human blood stem cells in the lab. Sarah Greenblatt, a postdoctoral associate in Nimer's group and co–first author of the study, used the structural information from Hoelz's group to create a mutated version of the protein. The Nimer group then introduced the mutated protein in blood stem cells, and found that the mutated DPF2 could no longer bind to the nucleosome. In other words, DPF2 could no longer inactivate the switch 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," says Huber. "Whether DPF2 can also be blocked in the cancer patients themselves remains to be seen." The researchers say a structural socket in DPF2, one of the puzzle–piece–like regions identified in the new study, is a good target for candidate drugs.