Genomic Insights into the Biology of T-lineage Acute Lymphoblastic Leukemia

Relapsed and refractory T-lineage acute lymphoblastic leukemia (T-ALL) has a poor prognosis, emphasizing the need to identify high-risk patients. T-ALL classification has relied on immunophenotype, including identification of early T-cell precursor ALL, but few genetic alterations reproducibly predict outcome in T-ALL independently of measurable residual disease. Here, the biologic and genetic basis of T-ALL is reviewed, with an emphasis on large-scale genomic analyses that have shed light on the spectrum of genetic subtypes, their drivers, mechanisms of oncogene activation, and developmental stage. We describe how genomics-based approaches can improve T-ALL classification and risk stratification.

Whole-genome and whole-transcriptome sequencing enable biologically and clinically meaningful T-ALL subtype classification with greater precision than immunophenotype-based approaches. The genomic landscape of T-ALL is heavily influenced by noncoding alterations, posing a challenge for clinical applications, as their detection often requires whole-genome sequencing. Studies have identified genomic subtypes and genetic alterations that improve the accuracy of patient outcome prediction.