Genomic characterization of childhood acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading case of childhood cancer death. The last decade has witnessed a transformation in our understanding of the genetic basis of ALL due to detailed integrative genomic profiling of large cohorts of childhood ALL. Initially using microarray based approaches, and more recently with next-generation sequencing, these studies have enabled more precise subclassification of ALL, and have shown that each ALL entity is characterized by constellations of structural and sequence mutations that typically perturb key cellular pathways including lymphoid development, cell cycle regulation, tumor suppression, Ras- and tyrosine kinase-driven signaling, and epigenetic regulation. Importantly, several of the newly identified genetic alterations have entered the clinic to improve diagnosis and risk stratification, and are being pursued as new targets for therapeutic intervention. Studies of ALL have also led the way in dissecting the subclonal heterogeneity of cancer, and have shown that individual patients commonly harbor multiple related but genetically distinct subclones, and that this genetically determined clonal heterogeneity is an important determinant of relapse. In addition, genome-wide profiling has identified inherited genetic variants that influence ALL risk. Ongoing studies are deploying detailed integrative genetic transcriptomic and epigenetic sequencing to comprehensively define the genomic landscape of ALL. This review describes the recent advances in our understanding of the genetics of ALL, with an emphasis on those alterations of key pathogenic or therapeutic importance.

Figure 1

Subclassification of childhood ALL. Blue wedges refer to B-progenitor ALL, yellow to recently identified subtypes of B-ALL, and red wedges to T-lineage ALL

Figure 2

Schema for the nature and timing of acquisitions of genetic alterations in the pathogenesis of B-ALL. It is likely that chromosomal rearrangements are acquired early in leukemogenesis, and drive transcriptional and epigenetic dysregulation and aberrant self-renewal. These lesions and/or secondary genetic alterations disrupt lymphoid development and result in an arrest in maturation. Additional genetic alterations target cellular pathways including cell cycle regulation, tumor suppression, cytokine receptor and kinase signaling, and chromatin modification. Diagnosis ALL samples are commonly clonally heterogeneous, and genetic alterations in minor clones may confer resistance to therapy and promote relapse. A similar schema can be proposed for T-ALL, where lesions targeting lymphoid development, self-renewal, and kinase signaling are also observed; and in which there are multiple targets of mutation of unknown role in leukemogenesis (e.g. PHF6, WT1).