The Proteomics of T-Cell and Early T-Cell Precursor (ETP) Acute Lymphocytic Leukemia: Prognostic Patterns in Adult and Pediatric-ETP ALL

Abstract

Background. The 5-year overall survival (OS) rates of T-cell lymphocytic leukemia (T-ALL) are better for children (>90%) compared to adults (~57%). The early T-cell precursor (ETP) T-ALL subtype is prognostically unfavorable in adults, but less significant in pediatric T-ALL, and the diagnosis and prognosis of “near”-ETP is controversial. We compared protein and RNA expression patterns in pediatric and adult T-ALL to identify prognostic subgroups, and to further characterize ETP and near-ETP T-ALL in both age groups. Methods. Protein expression was assessed using RPPA methodology for 321 target proteins in 361 T-ALL patient samples from 292 pediatrics and 69 adults, including 103 ETP-ALL. RNA-sequencing was performed on 81 pediatric T-ALL samples. Results. We identified recurrent protein expression patterns that classified patients into ten protein expression signatures using the “MetaGalaxy” analysis. In adults, Cox regression analysis identified two risk-groups associated with OS (p = 0.0002) and complete remission duration (p < 0.001). Cluster analysis of adults and pediatric-ETP patients identified three ETP-clusters strongly associated with age. Pediatric ETP-patients with a pediatric-dominant expression profile were associated with a shorter OS (p = 0.04) and event-free survival (p = 0.05) compared to pediatric ETP-patients with an ETP expression profile that was also identified in adults. Conclusion. Our study demonstrates that proteomics are predictive of outcome in adult T-ALL and that we can identify a small subset of pediatric ETP with an inferior outcome. The observation that there are age-specific patterns supports the idea that the origin of T-ALL in most pediatric and adult patients is different, while overlapping patterns suggests that there are some with a common pathophysiology. Proteomics could enhance risk stratification in both pediatric and adults with T-ALL.