Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.

Keywords: B-ALL; BCL11B; DUX4; IKZF1; NOTCH1; NUTM1; PAX5; Ph-like; T-ALL; ZNF384; genome; transcriptome.

Figure 1

This schematic algorithm for B-ALL subtyping was modified from the figure originally published in Paietta E. et al. Molecular Classification Improves Risk Assessment in Adult BCR-ABL1-negative B-ALL. Blood Prepublished Apr 25 2021; doi:10.1182/blood.2020010144 [83]. This figure describes each B-ALL subtype according to the specific genetic alterations and gene expression profile. Moreover, for each subtype peak prevalence and prognosis are shown. Subtypes are colored according to defining genetic alteration: gross chromosomal abnormalities (purple), transcription factor rearrangements (blue), other transcription factor alterations (blue), and kinase alterations (orange). Abbreviations: AYA, adolescent and young adult; tSNE, t-distributed stochastic neighbor embedding; TBD: to be defined; -R: rearranged.

Figure 2

T-cell differentiation and T-ALL subtyping. This schema describes differentiation stages of each T-ALL subtype according to the specific genetic alterations leading to aberrant expression of rearranged or mutated genes. Prevalence and prognosis of each subtype are shown. Subtypes are colored according to corresponding normal T-cell differentiation stage: early T-cell precursor (ETP, red and orange), early stages of cortical thymocytes maturation (green), and late stages of cortical thymocytes maturation (blue). Abbreviations: T-ALL: T-cell acute lymphoblastic leukemia; T/M MPAL: T/myeloid mixed phenotype acute leukemia; -R: rearranged.