Adult B-Cell Acute Lymphoblastic Leukaemia Antigens and Enriched Pathways Identify New Targets for Therapy

Abstract

Background: Adult B-cell acute lymphoblastic leukaemia (aB-ALL) is characterised by abnormal differentiation and proliferation of lymphoid progenitors. Despite a significant improvement in relapse-free and overall survival for children with B-ALL, aB-ALL has a particularly poor prognosis with a 5-year survival rate of 20%. First remission is achieved for most patients, but relapse is common with a high associated mortality. New treatments such as immunotherapy offer an opportunity to extend remission and prevent relapse. Methods: aB-ALL antigens were identified using different sources—immunoscreening, protoarrays, two microarrays and one cancer-testis antigen database, and a review of the genomic analyses of aB-ALL. A total of 385 aB-ALL-associated gene products were examined for their association with patient survival. Results: We identified 87 transcripts with differential expression between aB-ALL and healthy volunteers (peripheral blood, bone marrow and purified CD19+ cells), and 42 that were associated with survival. Enrichr analysis showed that the Transforming Growth Factor-β (TGFβ), Wnt and Hippo pathways were highly represented (p < 0.02). We found that SOX4 and ROCK1 were upregulated in all types of B-ALL (ROCK1 having a p < 0.001 except in t(8;14) patients), as well as SMAD3 and TEAD4 upregulation being associated with survival (p = 0.0008, 0.05 and 0.001, respectively). Expression of each aB-ALL antigen was verified by qPCR, but only TEAD4 showed significant transcript upregulation in aB-ALL compared to healthy volunteer CD19+ cells (p = 0.01). Conclusions: We have identified a number of antigens and their pathways that play key roles in aB-ALL and may act as useful targets for future immunotherapy strategies.