CREBBP is a Major Prognostic Biomarker for Relapse in Childhood B-cell Acute Lymphoblastic Leukemia: A National Study of Unselected Cohort.

Abstract

Although the identification of disease subtypes conveying prognostic significance along with minimal residual disease (MRD) assessment represent cornerstones for stratification in childhood acute lymphoblastic leukemia (ALL), approximately half of the relapses occur in patients from standard-risk groups. Identification of the drivers of treatment failure is crucial for detection of high-risk clones at diagnosis. We evaluated clinical variables and the most common genetic alterations in an unselected cohort of 55 patients with B-ALL treated according to the ALL-IC-BFM 2002 protocol, with a median follow-up of 46 months. Matched diagnosis-relapse samples underwent screening for additional alterations using whole-exome sequencing. Mutations in the CREBBP gene were found in 80% (4/5) of the patients with relapse, either present from the disease onset or acquired at relapse, while none of the examined patients in remission presented alterations in this gene. Deletions in TP53 and EBF1 (present in 2/5 and 1/5 of the patients with relapse, respectively) were infrequent or absent in the patients in remission, respectively. Screening for alterations in the CREBBP gene at diagnosis and/or at multiple time-points during chemotherapy could be incorporated into treatment protocols, as it may contribute to the identification of significant number of patients with predefined or acquired chemoresistant clones.