Genetic Risk Factors Affect Osteonecrosis Development in Pediatric ALL

Genetic variants increase the risk of osteonecrosis in children under age 10 with acute lymphoblastic leukemia (ALL), according to a new study.

Osteonecrosis is a limiting toxicity of ALL. Destruction of normal bone due to tissue death most frequently affects the knees, hips, and ankles, and results in pain and decreased mobility. This may require surgery, including core decompression and joint replacement, said Seth E. Karol, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee.

Dr. Karol presented the results of the study at the 57th Annual American Society of Hematology (ASH) Meeting and Exposition, held December 5–8 in Orlando, Florida (abstract 250).

Recent pediatric ALL trials have been amended to decrease osteonecrosis. This has precluded increased doses of steroids and asparaginase, drugs with fewer long-term side effects, he said.

Currently, the genetics of osteonecrosis in young children is incompletely understood, and the risk of the disease is highly age dependent. It occurs in 16% to 45% of patients over age 10, and in 3% to 10% of patients under age 10. “Children under age 10 make up 75% of new ALL diagnoses,” he said. “Despite the lower risk, children under age 10 make up about 40% of cases of osteonecrosis.”

Dr. Karol and colleagues formulated an analysis plan for osteonecrosis in children under age 10. They performed a genome wide association study (GWAS) of 1,186 children, including an initial discovery group of 82 patients with osteonecrosis and 287 patients who did not develop osteonecrosis, to identify genetic variants that are most common among those with the bone disease.

They observed that patients with osteonecrosis are 8 to 15 times more likely to possess genetic variants near a gene important to bone development (BMP7) and between 3 to 6 times more likely to have variants near a gene important to fat levels in the blood (PROX1).

The balance of bone and fat may be important in these patients, he said, and suggested that this may affect osteonecrosis through an effect on cholesterol levels.

“We found new genetic variants linked to an increased risk of osteonecrosis. The GWAS results were supported by pathway and enhancer enrichment analyses,” Dr. Karol said.

The two key findings, he said, are that glutamate receptor signaling was the top enriched pathway, with six genes present, including GRID2, and the adipogenesis pathway was the only other non-overlapping pathway, with seven genes, including BMP7 and BMP2.

He noted that GWAS single nucleotide polymorphisms were enriched in enhancers for bone marrow derived mesenchymal stem cells.

The findings suggest that certain genes are associated with increased risk of osteonecrosis in children under age 10. “Newly identified inherited variants in BMP7 and the adipogenesis pathway are associated with osteonecrosis,” said Dr. Karol. “While also important in younger children, inherited variants in glutamate receptor signaling genes appear to be more important in older children.”

He added that “these findings improve our understanding of osteonecrosis and will lead to further preclinical work to identify additional biomarkers and potential interventions to reduce osteonecrosis.”