Pediatric researchers studying the life-threatening blood disorder Fanconi anemia have devised a method to block the abnormal biological signals that drive the disease. This proof-of-concept finding in animals and stem cells from human cord blood may lay the foundation for better treatments for children with the rare, frequently fatal disease.

Pediatric researchers studying the life-threatening blood disorder Fanconi anemia (FA) have devised a method to block the abnormal biological signals that drive the disease. This proof-of-concept finding in animals and stem cells from human cord blood may lay the foundation for better treatments for children with the rare, frequently fatal disease.

"We showed how, in Fanconi anemia, an abnormal protein disruption to key growth pathway and damages the ability of bone marrow to produce blood cells," said study leader Wei Tong, Ph.D., a hematology researcher at Children's Hospital of Philadelphia.

Because inherited genetic mutations trigger bone marrow failure that reduces red blood cells counts in Fanconi anemia (FA) until recently children with the disorder rarely lived past age 10.

They have a high risk of leukemia and some solid tumors. To have a chance to survive, most children require a bone marrow transplant, but even that procedure is much more challenging than in other diseases.

FA results from a malfunction in DNA copying mechanisms. Each time a cell divides, the genetic information encoded in DNA is replicated and distributed to daughter cells. Scientists have known for years that FA is caused by mutations in one of 22 FA proteins, which normally work together to protect the integrity of genetic information.

New blood cells

Normally, Fanconi proteins are spell checkers, sensing errors and damage, and halting the copying machinery if there is a problem. This is particularlyimportant in the bone marrow, where stem cells divide frequently as they generate new blood cells.

If a mutation disables the "spell checking," the replication machinery keeps jamming, and errors accumulate that ultimately damage the DNA beyond repair. Unfortunately, intervening to correct the replication mechanism is difficult.

Gene therapy, which has shown promise in other blood disorders, would require extracting bone marrow cells, correcting them, and transplanting them back to the patient – a difficult process for patients with fragile bone marrow cells.

The new study suggests a different approach to the problem. The researchers used a mouse model of FA that lacks Fancd 2,a key protein in the FA pathway. Similar to FA patients, the mice show DNA damage and impaired blood stem cell activity.

In addition, the bone marrow cells do not transplant well. Tong and colleagues found that inhibiting a regulatory protein called Sh2b3 / Lnk restored the ability of the abnormal bone marrow cells to transplant and grow in mic. Inhibiting Lnk also improved the proliferation and survival of blood cells and crucially improved genome integrity.