January 31, 2019

Cell death pathway implicated in bone marrow failure

Vanderbilt investigators have linked a specific form of programmed cell death to myelodysplastic syndrome, a type of bone marrow failure.

From left, Sandra Zinkel, MD, PhD, Christi Salisbury-Ruf, MS, Patrice Wagner, PhD, Jing Zou, MD, PhD, and Yuliya Hassan have linked a specific form of programmed cell death to myelodysplastic syndrome, a type of bone marrow failure.

The production of blood cells in the bone marrow — hematopoiesis — requires a careful balance between cell division, maturation and death.

Vanderbilt investigators have now discovered that disrupting that balance and pushing cells to die a certain way, by a pathway called necroptosis, leads to bone marrow failure in mice that resembles the human disease myelodysplastic syndrome (MDS). Their study, featured as a Plenary Paper in the journal Blood, implicates necroptotic signaling in MDS and points to new therapeutic opportunities for the disease.

The team’s research was featured on the journal’s cover. The image shows the expression of a specific cell death signaling protein in bone marrow from a patient with myelodysplastic syndrome.

In MDS, cells in the bone marrow are abnormal (dysplastic) and do not form healthy blood cells. It is most commonly diagnosed in older individuals, and in some patients, MDS progresses to acute myeloid leukemia.

“For MDS, we have few treatments to offer patients, and response rates to the treatments we do have are generally very low,” said Sandra Zinkel, MD, PhD, associate professor of Medicine and Cell and Developmental Biology.

Zinkel and her colleagues have focused on the role of programmed cell death — cell death mediated by a regulated sequence of signaling events — in blood production in the bone marrow.

Two types of programmed cell death, called apoptosis and necroptosis, have been characterized. Cells that die by apoptosis “implode.” They are digested by internal enzymes, collapse, and are removed without creating a scene. Cells that die by necroptosis, on the other hand, “explode.” They dump their contents and generate inflammation.

“There are several types of bone marrow failure that are characterized by increased inflammation, and we wanted to know whether inflammatory programmed cell death, necroptosis, might be playing a role,” Zinkel said. “So, we genetically rigged it so that the bone marrow cells in a mouse would die by necroptosis.”

Mice with increased bone marrow necroptosis, driven by a protein called Rip1 kinase, had a loss of progenitor cells in the bone marrow, increased inflammatory factors and increased immature, abnormal cells. The mice died from bone marrow failure.

When the researchers, led by former and current graduate students Patrice Wagner, PhD, and Christi Salisbury-Ruf, MS, genetically reduced Rip1 kinase to normal levels, the mice had normal red blood cell counts and normal levels of inflammatory factors, and they survived.

The team examined human MDS bone marrow samples and found increased levels of necroptotic signaling proteins (Rip1 kinase and MLKL) and evidence of necroptotic cell death by electron microscopy.

Inhibitors of Rip1 kinase — the signaling protein driving necroptosis — are currently in clinical trials for other diseases, Zinkel said.

“Our study suggests that MDS is a disease where Rip1 kinase inhibitors should be studied,” she said. “It’s very early, but it’s exciting to potentially have a new treatment option for patients with MDS.”

The researchers also tested the anti-inflammatory drug etanercept (Enbrel) in the mice with MDS-like disease. They found that this treatment partially restored bone marrow progenitor cells and reduced anemia.

“It’s possible that an anti-inflammatory drug like Enbrel that’s already clinically approved could help MDS patients. That might be more straightforward than getting a new drug approved,” Salisbury-Ruf said.

“It seems that in MDS the marrow has gotten skewed to too much death and too much inflammation,” Zinkel said. “If we can rebalance the marrow, either by inhibiting Rip1 kinase and necroptosis or by reducing the inflammation, that might restore the marrow’s function.”

The researchers will continue to characterize the mouse model to understand what happens to specific cell types in the bone marrow during MDS-like disease progression. They also plan to use BioVU, Vanderbilt’s DNA biobank linked to electronic health records, to explore genetic risk factors for MDS and the potential of anti-inflammatory medications to treat the disease.

“The take-home message is that MDS has a necroptotic arm,” Salisbury-Ruf said. “No one appreciated that necroptosis was playing a role, and that really changes the way we think about this disease and gives us targets for new treatments.”

The team’s study was featured on the journal cover and as a Plenary Paper, a designation made by the journal editors to highlight “definitive original research articles of exceptional scientific importance.”

This research was supported by the National Institutes of Health (grants HL088347, HL133559), the American Society of Hematology, the U.S. Department of Veterans Affairs (Merit Award), and the Edward P. Evans Foundation.