Photo courtesy of St. Jude
Researchers say they have identified a mechanism that helps leukemia cells resist glucocorticoids.
They believe the mechanism is responsible for about a third of steroid resistance in children and adolescents with acute lymphoblastic leukemia (ALL).
However, additional research is needed to determine if the process is at work in adults with ALL, where steroid resistance is more common and long-term survival lags.
The researchers described the mechanism in Nature Genetics.
“Based on these findings, research has already begun to identify small molecules with the potential to reverse glucocorticoid resistance, leading to more effective treatment and increased survival,” said study author William Evans, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
Dr Evans and his colleagues analyzed samples from 444 newly diagnosed ALL patients being treated at St. Jude or in clinical trials sponsored by the Dutch Childhood Oncology Group and the German Cooperative Study Group for Childhood ALL.
The team also analyzed samples collected at diagnosis and relapse from 49 pediatric ALL patients enrolled in clinical trials organized by the Children’s Oncology Group.
The researchers found differences in gene expression that correlated with sensitivity to steroids. CASP1 and NLRP3 were among the genes with increased activity in steroid-resistant leukemia cells.
The team also identified a reason for the increased gene activity. Leukemia cells overexpressing CASP1 and NLRP3 had lower levels of methylation compared to cells with normal expression.
Previous research showed that steroid resistance was more common in young ALL patients who relapsed than in newly diagnosed patients. Dr Evans and his colleagues found that expression of CASP1 and NLRP3 was significantly higher in ALL patients who relapsed.
The researchers also discovered that CASP1 blocks glucocorticoids by splitting the receptor where the drug binds and therefore blocks its access to the nucleus.
“Cells that overexpress CASP1 are chewing up their glucocorticoid receptor,” Dr Evans said. “That means when steroids enter the cell, there is no receptor for the drugs to bind to or fulfill its therapeutic function.”
To confirm that CASP1 cleavage of the steroid receptor is pivotal to ALL steroid resistance, the researchers engineered a receptor that lacked the CASP1 cleavage site. When they introduced the genetically engineered receptors into ALL cells that expressed high levels of CASP1, the cells remained sensitive to steroids.
Using a variety of techniques, the researchers showed that steroid resistance rose or fell in leukemia cells based on CASP1 levels. Overexpression of CASP1 rendered ALL cells 5 to 15 times more resistant to the glucocorticoids dexamethasone and prednisolone.
However, reducing CASP1 using genetic, pharmacologic, and other methods restored steroid sensitivity in leukemia cells.
