Identification of survivin as a promising target for the immunotherapy of adult B-cell acute lymphoblastic leukemia.

Laurie Freire Boullosa,Laurence Orchard,Ken I Mills,Evelien Smits,Hannah Wickenden,Cindy Lee,Barbara-Ann Guinn,Payalben Savaliya,Alison H Banham,Kim Orchard,Stephanie Bonney

doi:10.18632/oncotarget.23380

Abstract

B-cell acute lymphoblastic leukemia (B-ALL) is a rare heterogeneous disease characterized by a block in lymphoid differentiation and a rapid clonal expansion of immature, non-functioning B cells. Adult B-ALL patients have a poor prognosis with less than 50% chance of survival after five years and a high relapse rate after allogeneic haematopoietic stem cell transplantation. Novel treatment approaches are required to improve the outcome for patients and the identification of B-ALL specific antigens are essential for the development of targeted immunotherapeutic treatments.We examined twelve potential target antigens for the immunotherapy of adult B-ALL. RT-PCR indicated that only survivin and WT1 were expressed in B-ALL patient samples (7/11 and 6/11, respectively) but not normal donor control samples (0/8). Real-time quantitative (RQ)-PCR showed that survivin was the only antigen whose transcript exhibited significantly higher expression in the B-ALL samples (n = 10) compared with healthy controls (n = 4)(p = 0.015). Immunolabelling detected SSX2, SSX2IP, survivin and WT1 protein expression in all ten B-ALL samples examined, but survivin was not detectable in healthy volunteer samples. To determine whether these findings were supported by the analyses of a larger cohort of patient samples, we performed metadata analysis on an already published microarray dataset. We found that only survivin was significantly over-expressed in B-ALL patients (n = 215) compared to healthy B-cell controls (n = 12)(p = 0.013).We have shown that survivin is frequently transcribed and translated in adult B-ALL, but not healthy donor samples, suggesting this may be a promising target patient group for survivin-mediated immunotherapy.

Highlights

Acute lymphoblastic leukemia (ALL) is characterized by an excess of lymphoblasts of either the B- or T-lineage
We examined the expression of twelve antigens (BCP-20, G250, HAGE, END, NY-ESO-1, PAS domain-containing protein 1 (PASD1), p68 RNA helicase, SSX2, SSX2 interacting protein (SSX2IP), survivin, tyrosinase and Wilms tumor-1 (WT1)), identified as promising through a review of the literature, in human cancer cell lines to demonstrate consistency with previously published data and to optimise our assays (Supplementary Table 1)
We examined the expression of the same twelve antigens in thirteen samples from eleven adult B-cell acute lymphoblastic leukemia (B-ALL) patients and eight healthy volunteers (Table 1)

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is characterized by an excess of lymphoblasts of either the B- or T-lineage. While the improvement in survival post-allogeneic HSCT may in part be due to the use of intensive chemotherapy and radiotherapy (such as total body irradiation) as conditioning, there does appear to be an increased survival advantage following HSCT using reduced intensity conditioning schedules in older patients and those with co-morbid risk factors [4, 5]. This suggests that post-transplant mechanisms, probably immunological in nature, play an important role in disease control with graft versus leukemia (GvL) effective in the eradication of residual disease. The ‘GvL effect’ has been demonstrated in other haematological malignancies, chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and myeloma, with the identification of probable immunological targets such as minor histocompatibility antigens [6], tumor specific antigens [7] and cancer-testis antigens (CTAs) [8]

Methods

Results

Conclusion