Childhood acute lymphoblastic leukemia: Integrating genomics into therapy

Abstract

Acute lymphoblastic leukemia (ALL), the most common malignancy of childhood, is a genetically complex entity that remains a major cause of childhood cancer-related mortality. Major advances in genomic and epigenomic profiling during the past decade have appreciably enhanced knowledge of the biology of de novo and relapsed ALL and have facilitated more precise risk stratification of patients. These achievements have also provided critical insights regarding potentially targetable lesions for the development of new therapeutic approaches in the era of precision medicine. In this review, the authors delineate the current genetic landscape of childhood ALL, emphasizing patient outcomes with contemporary treatment regimens as well as therapeutic implications of newly identified genomic alterations in specific subsets of ALL.

Keywords: acute lymphoblastic leukemia; cytogenetics; genomics; pediatrics; therapy.

Figure 1. Frequency of cytogenetic alterations in childhood B-ALL and T-ALL

Data regarding submicroscopic genetic alterations are not included.

Figure 2. Impact of genetic features of ALL upon therapy response

Chemosensitive ALL cells (pale blue) respond to appropriately intensive chemotherapy based upon underlying leukemic genetics and risk stratification, often allowing patients to achieve sustained remission. Chemoresistant ALL cells (dark blue) may result from inherently drug-resistant subclones present at diagnosis or from selective pressure during chemotherapy that leads to development of acquired mutations and facilitates relapse. Very rarely, secondary malignancies may arise from genetically distinct subclones than those present at diagnosis.