PDK1 plays a starring role in the life of B cells

By Guest Blogger

This post was written  by Kelly Chi,  a science writer.

A new study shows just how critical a particular signaling molecule, phosphoinositide-dependent kinase-1 (PDK1), is for the development, survival, and activation of B cells. B cells are constantly circulating in our blood, and they are critical for immune function by producing antibodies to combat infection. At certain stages of their differentiation, they are induced to proliferate—but they can mutate and grow uncontrollably, causing cancer. The study zeroes in on times in a B cell’s life when PDK1 is especially important. Published June 16 in Proceedings of the National Academy of Sciences, the results will inform new treatments for B-cell cancers.

Present in every cell and responsible for many facets of metabolism, the enzyme PDK1 and the molecules in its path are already targets in the development of drugs for cancer. An enzyme upstream of PDK1, for example, PI3K (phosphoinositide 3-kinase), has shown promise as a target in B-cell chronic lymphocytic leukemia and other B-cell cancers. Blocking these molecules with drugs may help slow or stop the growth of B-cell cancers, though scientists are still trying to figure out how exactly they work.

“In the PI3K signaling cascade, what strikes you is that PDK1 is this pivotal enzyme,” said lead author Robert Rickert, Ph.D., professor and director of the Immunity and Pathogenesis Program at Sanford-Burnham. Although PI3K has been shown to be critical for B-cell growth and survival, not as much was known about PDK1’s role in these cells.

In adults, the cells that give rise to B cells start out in the bone marrow and undergo a number of cell-signaling events. A “mature” B cell then moves into the bloodstream and the lymphoid tissues, where it waits for a signal from an antigen to begin the important job of churning out antibodies.


Three mutant mice

In the new study, Rickert and his collaborators at the Max Planck Institute for Immunobiology and Epigenetics in Freiburg, Germany, took advantage of several new mouse mutants in which PDK1 is deleted at different stages of B-cell development. The first type of mouse mutant they investigated was missing PDK1 in its B-cell progenitors—dividing cells that are committed  to become B cells. In these animals, the B cells-to-be never matured or made it out of the bone marrow and into circulation.

Looking more closely at the cells in a culture dish, the group could see where the block was. They identified three molecules in PDK1’s path that seem to be key for early B-cell survival—so, said Rickert, “we don’t think there’s one single survival factor that PDK1 regulates.” The second mouse mutant the team used was missing PDK1 in newly mature B cells as they are leaving the bone marrow. At this stage, they are considered “resting” cells, and in the mouse, they die after eigh weeks if they’re not contributing to an immune response. Studies show that mature B cells need a constant, low level of stimulation to survive those weeks. But without PDK1, these cells did not get sufficient stimulation and died within a few days.

“The importance of PDK1 for survival was somewhat surprising,” said Rickert, “especially because the enzyme is not shown to be critical for maintenance of T cells, another big player in the immune system.”

The third type of mouse was an “inducible” model, meaning researchers could switch off PDK1 at will, with injection of a drug. In this case, they were able to target mature B cells. “That was helpful because we could knock out PDK1 during an immune response,” said Rickert. “We knew that we’d have enough B cells, they’d have PDK1, they are perfectly normal, and then, when we inject a drug, PDK1 would be deleted very quickly.” These animals were not able to generate antibody responses to a pathogen.

Cautions with complexity

Interestingly, however, some mature B cells in the mice were a bit stubborn. Just a small amount of remaining PDK1 seemed to be sufficient for their survival. “Even if deletion of PDK1 was greater than 90 percent, if 5 or 10 percent of the protein remained, it was sufficient for some of the B cells to survive or respond,” Rickert said. That means developing a drug that inhibits PDK1 sufficiently could be challenging.

In addition, PDK1 acts independently of PI3K, and both are embedded in complex, branching molecular pathways—suggesting that cells could find different ways of compensating if a single player is blocked. If multiple pathways are involved in survival, then a combination of chemical inhibitors might be the best general treatment strategy, Rickert said.

The team plans to create yet another mutant mouse for future studies investigating the effects of blocking PDK1 on the progression of B-cell cancers.

A link to the paper can be found at http://www.pnas.org/content/early/2014/06/11/1314562111.abstract?sid=f84bcc42-6db2-4d17-9c33-96b7a05127cb.

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