Molecular origin of childhood acute lymphoblastic leukemia

Our understanding of the genetic etiology of pediatric acute lymphoblastic leukemia (ALL) has advanced greatly in the past few decades. Due to the advent of genome-wide profiling techniques for copy number alterations (CNAs) as well as sequence mutations, we have thoroughly characterized many different genetic subtypes of ALL. Each subtype harbors alterations activating leukemogenic pathways and differs in prevalence, prognosis, cell type, and treatment response. The interplay of founding leukemogenic aberrations, acquired mutations, and germline composition of the patient is important for the development and progression of the disease. Moreover, genomic profiling has identified genetic alterations that have been integrated into diagnostic testing algorithms and are being evaluated as targets for therapy. Despite these advances, the genetic basis of a minority of ALL cases remains unknown, and the frequency of these enigmatic cases rises with patient age. Much work remains in studying these last uncharacterized groups to fully understand leukemia development and improve outcomes.