Expanding Beyond Genetic Subtypes in B-Cell Acute Lymphoblastic Leukemia: A Pathway-Based Stratification of Patients for Precision Oncology

Abstract

Precision oncology promises individually tailored drugs and clinical care for patients with cancer: That is, the right drug, for the right patient, at the right dose, and at the right time. Although stratification of the risk for treatment resistance and toxicity is key to precision oncology, there are multiple ways in which such stratification can be achieved, for example, genetic, functional pathway based, among others. Moving toward precision oncology is sorely needed in the case of acute lymphoblastic leukemia (ALL) wherein adult patients display survival rates ranging from 30% to 70%. The present study reports on the pathway activity signature of adult B-ALL, with an eye to precision oncology. Transcriptome profiles from three different expression datasets, comprising 346 patients who were adolescents or adults with B-ALL, were harnessed to determine the activity of signaling pathways commonly disrupted in B-ALL. Pathway activity analyses revealed that Ph-like ALL closely resembles Ph-positive ALL. Although this was the case at the average pathway activity level, the pathway activity patterns in B-ALL differ from genetic subtypes. Importantly, clustering analysis revealed that five distinct clusters exist in B-ALL patients based on pathway activity, with each cluster displaying a unique pattern of pathway activation. Identifying pathway-based subtypes thus appears to be crucial, considering the inherent heterogeneity among patients with the same genetic subtype. In conclusion, a pathway-based stratification of the B-ALL could potentially allow for simultaneously targeting highly active pathways within each ALL subtype, and thus might open up new avenues of innovation for personalized/precision medicine in this cancer that continues to have poor prognosis in adult patients compared with the children.