Blocking two proteins could improve stem cell transplants for blood cancers

Transplants of hematopoietic, or blood-forming, stem cells can be used to treat blood cancers or cancers of the immune system. But the procedure puts stress on the stem cells, causing many of them to die. To solve this problem, researchers in Germany temporarily inhibited two proteins in mice, preventing stem cells from dying and limiting side effects.

Stem cell transplants are a treatment option for cancer patients whose bone marrow is no longer able to make blood cells. This can happen as a result of the cancer itself—in the case of blood cancers or cancers of the immune system—or from the chemotherapy and/or radiation used to treat the disease.

Stem cell transplants sometimes fail because too many of the cells die before the transplant takes. And even if the cells succeed in establishing themselves in the bone marrow, the patient isn’t out of the woods yet. Patients face the risk of infection, inflammation, bleeding and graft-versus-host disease, where the immune system rejects the donor stem cells as foreign, according to the American Cancer Society.

Hematopoietic stem cells (HSCs) die via apoptosis, or programmed cell death, which is driven by the proteins BIM and BMF. The researchers tried permanently blocking these proteins in mice. That stopped the HSCs from dying and improved the efficiency of HSC transplant. But it also caused the mice to develop lymphomas and/or autoimmune disease because the modified stem cells did not die on schedule.

Next, the team infected mouse HSCs with a genetically engineered virus that briefly produces a human protein that blocks BIM and BMF. This treatment made the HSCs resistant to apoptosis for seven to nine days, allowing them to ensconce themselves in the mice’s blood marrow and make new blood cells. But because the stem cells were only apoptosis-resistant for a short period, they did not encourage lymphomas to form.

The findings are published in The Journal of Experimental Medicine.

"Our findings suggest that transiently inhibiting apoptosis by manipulating donor HSCs increases the fitness of these cells without elevating the risk of adverse pathology," says Miriam Erlacher, one of the study's authors. "Transient apoptosis inhibition is therefore a promising approach to reduce the risk of graft failure and improve HSC transplantation outcomes."