Curbing a hard-to-treat leukemia

DNA packaging provides a target for leukemia Giving chromosomes their structure and shape, strands of DNA, shown in gray, are coiled around histones, depicted as spheres. In MLL-rearranged acute lymphoblastic leukemia ALL, a form of acute lymphoblastic leukemia affecting infants, an enzyme call DOT1L modifies the histones in an abnormal way (as indicated in orange) that activates cancer-promoting genes. Drugs inhibiting DOT1L could prevent a variety of cancerous changes in cells.

While cure rates for most childhood leukemias are about 80 percent, they are much lower for children with a subtype of acute lymphoblastic leukemia (ALL), accounting for 70 percent of ALLs in infants, in which a gene called MLL is mutated. Now, a study led by Scott Armstrong, MD, PhD, Andrei Krivtsov, PhD and Zhaohui Feng of Children's Hematology/Oncology Department suggests a relatively easy way of preventing cancer-causing genes from turning on.

In a paper in the November 4 Cancer Cell, they show that the abnormal protein that characterizes the disease, called MLL-AF4, goes to a white blood cell's DNA and alters one of the "scaffolding" proteins, known as histones, that the strands of DNA are wrapped around. The change alters the structure of the chromosome, jump-starting a diverse group of genes that normally aren't turned on, including some that are critical in initiating leukemia.

While MLL-AF4 itself would be difficult to target chemically, it turns out that the protein does its evil work via an enzyme called DOT1L, a much easier target. It therefore might be possible to silence a variety of genes that contribute to malignancy in a single chemical maneuver. Armstrong's lab is now searching for small-molecule drugs that inhibit DOT1L. "Reversal of histone modifications could be an important therapeutic approach for MLL-AL4 and potentially for other cancers," Armstrong says.

Forcing cancer cells to self-destruct

Another study, led by Loren Walensky, MD, PhD, attending physician in Hematology/Oncology, found a switch on a naturally occurring "death protein" called BAX, which normally helps the body get rid of unwanted or diseased cells. By activating this switch, Walensky and colleagues tricked cells into committing suicide. "We believe this discovery can be used to develop cancer drugs that turn on cell death by targeting BAX," said Walensky, whose lab is at the Dana-Farber Cancer Institute. The study was published in the October 23 Nature.

Reviving nerves' ability to regenerate

	Silencing the growth inhibitor gene, PTEN, in mice promotes dramatic optic nerve regeneration (right image) after injury, as compared with control mice. The injury site is marked by an asterisk (*).

Because injured neurons in the brain or spinal cord can't grow back, damage from spinal cord injury, stroke or other forms of brain injury can't be repaired. But researchers led by Zhigang He, PhD, a neurologist at Children's Hospital Boston, have found a way to overcome natural inhibitory mechanisms that suppress regeneration, causing nerve fibers to re-grow vigorously.

Previous studies, including some from He's lab, tried to spur re-growth by removing inhibitory molecules from the neurons' environment. But this approach had only modest effects. He's team, collaborating with Children's neurologist Mustafa Sahin, MD, PhD, now shows that re-growth is primarily regulated from inside the cells. Using genetic techniques, the researchers deleted two of these internal regulators in mice with injured optic nerves. This allowed a growth pathway called mTOR—normally silenced in mature neurons—to become active again. As a result, up to 50 percent of injured neurons survived, versus about 20 percent in mice without the genetic deletions. Up to 10 percent of the mice showed significant, long-distance re-growth of nerve fibers.

He believes it may be possible to accomplish the same re-growth with drugs. But the next step is to determine whether the regenerating fibers can actually restore function. Kevin Park, PhD, Kai Liu, PhD, Yang Hu, PhD, and Patrice Smith, PhD, all of Neurobiology, were coauthors on the paper, published in Science on November 7.