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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most frequent childhood tumor and despite cure rates exceeding 90% in children, outcomes for older children and adults remain poor with cure rates below 40% in those over the age of 40 [1,2,3], despite pediatricinspired chemotherapy regimens [4]
ALL may be of B- (B-ALL) or T-lymphoid (T-ALL) lineage, and comprises over thirty distinct subtypes characterized by germline and somatic genetic alterations that converge on distinct gene expression profiles [5,6,7,8,9,10,11,12]
These subtypes are defined by disease-initiating recurrent chromosomal gains and losses; chromosomal rearrangements that deregulate oncogenes or encode chimeric fusion oncoproteins, importantly often including cryptic rearrangements not identifiable by conventional cytogenetic approaches, such as DUX4 and EPOR rearrangements; subtypes defined by single point mutations (e.g., PAX5 P80R or IKZF1 N159Y); subtypes defined by enhancer hijacking (e.g., BCL11B-rearrangements in T-Cell Acute Lymphoblastic Leukemia (T-ALL) and lineage ambiguous leukemia) [5]; and subtypes that “phenocopy” established subtypes, with similar gene expression profile but different founding alterations
Summary
Acute lymphoblastic leukemia (ALL) is the most frequent childhood tumor and despite cure rates exceeding 90% in children, outcomes for older children and adults remain poor with cure rates below 40% in those over the age of 40 [1,2,3], despite pediatricinspired chemotherapy regimens [4] This discrepancy is in part attributable to the different prevalence of genetic alterations across age. Accurate identification of the genetic abnormalities that drive ALL is important to risk stratify disease, and to guide the incorporation of molecular targeted therapeutic approaches to reduce the risk of relapse This has been previously relied upon conventional karyotyping, fluorescence in situ hybridization (FISH) and targeted-molecular analyses. T-ALL, highlighting their genetic characterization and diagnostic classification, clinical features, and therapeutic implications
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