CREBBP Gene Mutations Associated With Resistance and Relapse in Childhood ALL

Children with acute lymphoblastic leukemia (ALL) who have mutations in the CREBBP gene are more likely to relapse according to a team of researchers with St. Jude Children's Research Hospital and the National Cancer Institute. The CREBBP gene produces CREB binding protein, an enzyme involved in cell growth and division. According to the investigators, CREBBP also regulates genes essential to normal blood cell development.

 

The team of scientists has been tracking an array of 300 genes in 23 children with ALL. Each gene is sequenced at diagnosis and at relapse, and the sequences are analyzed against DNA sequencing in the patient's normal cells. The process has already been used to identify 52 somatic mutations in 32 genes, including 4 in the CREBBP gene.

 

For the study, the researchers analyzed the genes of 341 patients with leukemia for CREBBP mutations or deletions. Approximately 18% of the 71 children with ALL who had relapsed demonstrated alterations in the CREBBP gene; 13 patients had changes and 2 had deletions. A total of 14 CREBBP mutations were identified. Some have already been found to cause inherited conditions and others have previously been associated with response to steroids or the acetylation process.

 

According to the authors, the gene mutations were evident at diagnosis and persisted through relapse in some patients. In other patients, the gene mutations were observed only after relapse, but in leukemia cells present at diagnosis. Of 200 ALL and acute myeloid leukemia patients who did not relapse, only 1 was found to harbor a CREBBP mutation. 

 

In vitro studies of CREBBP-mutated cells from 9 subtypes of ALL revealed that most of the cells were resistant to dexamethasone but sensitive to vorinostat, which has a different mechanism of action.

 

The investigators hypothesized that the CREBBP gene might be useful in predicting relapse risk for patients with ALL. They are also planning a study to test vorinostat in mouse models of relapsed ALL. Complete findings appear in the March 10 issue of Nature.