Recurrent patterns of protein expression signatures in pediatric acute lymphoblastic leukemia: recognition and therapeutic guidance

Abstract

Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, and the second leading cause of pediatric cancer death in developed countries. While the cure rate for newly-diagnosed ALL is excellent, the genetic heterogeneity and chemoresistance of leukemia cells at relapse makes individualized curative treatment plans difficult. We hypothesize that genetic events would coalesce into a finite number of protein signatures that could guide the design of individualized therapy. Custom Reverse Phase Protein Arrays were produced from 73 pediatric ALL and 10 normal CD34+ samples with 194 validated antibodies. Proteins were allocated into 31 Protein Functional Groups (PFG) to analyze them in the context of other proteins, based on known associations from the literature. The optimal number of protein clusters was determined for each PFG. Protein networks showed distinct transition states, revealing “normal-like” and “leukemia-specific” protein patterns. Block clustering identified strong co-correlation between various protein clusters that formed 10 protein constellations. Patients that expressed similar recurrent combinations of constellations compiled 7 distinct signatures, correlating with risk stratification, cytogenetics and laboratory features. Most constellations and signatures were specific for T-cell ALL or pre-B-cell ALL, however some constellations showed significant overlap. Several signatures were associated with Hispanic ethnicity, suggesting that ethnic pathophysiological differences likely exist. Additionally, some constellations were enriched for “normal-like” protein clusters, whereas others had exclusively “leukemia-specific” patterns.