The epigenome in pediatric acute lymphoblastic leukemia: drug resistance and therapeutic opportunities

Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. The genomic landscape of pediatric ALL has been extensively characterized, allowing for the identification of distinct molecular subtypes of this disease. This in turn has facilitated improvements in risk stratification and tailoring of therapy, resulting in dramatic improvements in survival rates over the past several decades. However, despite these improvements, outcomes remain dismal for the ten percent of patients who continue to fail therapy and relapse. Although the genetic landscape of pediatric ALL is well-understood, increasing evidence suggests that genetic alterations alone are insufficient to promote leukemogenesis and the acquisition of chemoresistance that leads to disease relapse. Instead, cooperating epigenetic alterations are now recognized as important contributors to the aberrant gene expression profiles that are characteristic of the molecular subtypes of ALL, and changes in the epigenetic landscape are now thought to underlie the development of chemoresistance and ultimately disease relapse. This review article focuses on the expanding knowledge of the role of the epigenome in ALL pathogenesis, progression, and response to therapy, and highlights preclinical and clinical efforts to target the epigenome as a means of overcoming chemoresistance and improving outcomes for children with ALL.