New targets for therapy: antigen identification in adults with B-cell acute lymphoblastic leukaemia

Abstract

Acute lymphoblastic leukaemia (ALL) in adults is a rare and difficult-to-treat cancer that is characterised by excess lymphoblasts in the bone marrow. Although many patients achieve remission with chemotherapy, relapse rates are high and the associated impact on survival devastating. Most patients receive chemotherapy and for those whose overall fitness supports it, the most effective treatment to date is allogeneic stem cell transplant that can improve overall survival rates in part due to a 'graft-versus-leukaemia' effect. However, due to the rarity of this disease, and the availability of mature B-cell antigens on the cell surface, few new cancer antigens have been identified in adult B-ALL that could act as targets to remove residual disease in first remission or provide alternative targets for escape variants if and when current immunotherapy strategies fail. We have used RT-PCR analysis, literature searches, antibody-specific profiling and gene expression microarray analysis to identify and prioritise antigens as novel targets for the treatment of adult B-ALL.

Keywords: B-cell acute lymphoblastic leukaemia; BMX; Immunotherapy; PIVAC19; Survivin; Tumour antigens.

Fig. 1

Protein microarray analysis of sera from B-ALL patients and healthy donors was used to demonstrate which antigens were more frequently recognised by healthy donor or patient sera. a A representative protein microarray slide after immunoscreening with 10 ul of patient sera and analysis on the ScanArray Xpress while, b a Venn diagram summarising the number of antigens that were significant in their recognition by patient versus healthy volunteer sera (p ≥ 0.02). We were particularly interested in antigens that were preferentially recognised by patient sera as these are likely to provide targets for immunotherapy, however antigens with differential recognition by patient versus healthy donor sera also provided unique insights into the biological processes that underlie adult B-ALL

Fig. 2

Key interactions of BMX and its pathways. The interactors by which BMX can mediate these pathways are indicated next to the pathway. The interactors and pathways that are involved in the oncogenic cellular phenotype are coloured yellow; those involved in cell differentiation are coloured red; those involved in the immune response and/or inflammation are coloured green; while those coloured in blue are the members of the Tec family of non-receptor tyrosine kinases. TEC encodes the angiopoietin-1 receptor, ITK gene encodes interleukin-2-inducible T-cell kinase; TXK encodes tyrosine-protein kinase protein and BTK encodes Bruton’s tyrosine kinase

Fig. 3

mRNA expression analysis from AML, ALL and preleukemic stages when compared to healthy bone marrow in the leukaemia MILE study. Transcripts of (a) survivin were decreased with high significance compared with healthy bone marrow (p < 0.001) in all patient groups except MDS and B-ALL with t(8;14) which were not significant, ALL t(1;19) which was significant (p < 0.05) and ALL complex and T-ALL which were significant to p < 0.01; b BMX was significantly lower with p values of < 0.001 for all groups compared with healthy bone marrow except c-/Pre-B-ALL t(9;22) (p < 0.05), and MDS (not significant). Cells were from GSE13159 and the data shown was generated by BloodSpot [52]. Y-axis indicates log₂ expression. Each circle represents one sample analysed and the red box on each graph indicates the expression of the antigen in healthy bone marrow