Comparative proteomics uncovers vital molecular players of central nervous system leukemia among Mexican pediatric patients

Acute lymphoblastic leukemia (ALL) is the most common pediatric hematologic malignancy. The leukemic cells start in the bone marrow and spread to other vital organs and tissues, including the central nervous system (CNS). Hispanic males are the community with the highest incidence of ALL. Unfortunately, there is limited information on the molecular signatures of leukemic cell infiltration into the CNS, which marks the progression from ALL to central nervous system leukemia (CNSL). To address this knowledge gap, we performed a label-free shotgun proteomics between the cerebrospinal fluid (CSF) from patients with ALL compared to those with confirmed CNSL. We were able to identify 619 proteins, including 340 proteins that had not been reported prevously in the CSF of subjects with CNSL. The major features associated with CNSL included the over-accumulation of cell-adhesion proteins such as L-selectin and several cadherin proteins, along with the modulation of enzymes associated with protein glycosylation, which may provide the appropriate conditions for leukemic cell infiltration into the CNS. The over-accumulation of proteins associated with ROS scavenging processes reveals hypoxic and redox homeostasis microenvironment conditions that favors ALL progression to CNSL. The further characterization of key differential proteins will be essential for establishing reliable molecular markers for CSNL.

Biological significance

Central nervous system leukemia (CNSL) is a catastrophic progression of ALL defined by leukemic cells reaching the CNS. Limited comparative proteomics studies have been conducted previously between patients with ALL versus CNSL. While these studies were important pioneering steps, they were hindered by difficulties in obtaining the proper amount of protein samples related to CSF. They were based on minimal study subjects, and their proteomics pipelines did not include the depletion of high-abundance proteins. Defining the manners in which the CNSL proteome is perturbed compared to the ALL condition is paramount to understanding the molecular foundations of CNSL and identifying and characterizing protein markers for proper diagnosis. Improving the sensitivity and reliability of diagnosis using molecular markers would help clinicians to maximize patient outcomes and quality of life by implementing aggressive CNSL treatments as soon as possible in cases where infiltration has occurred, while avoiding exposure to toxic chemotherapies in patients where they are not yet necessary.