Serum profiling identifies ibrutinib as a treatment option for young adults with B‐cell acute lymphoblastic leukaemia

Abstract

Acute lymphoblastic leukaemia (ALL) is a haematological malignancy that is characterized by the uncontrolled proliferation of immature lymphocytes. 80% of cases occur in children where ALL is well understood and treated. However it has a devastating affects on adults, where multi-agent chemotherapy is the standard of care with allogeneic stem cell transplantation for those who are eligible. New treatments are required to extend remission and prevent relapse to improve patient survival rates. We used serum profiling to compare samples from presentation adult B-ALL patients with age-and sex-matched healthy volunteer (HV) sera and identified 69 differentially recognised antigens (P ≤ 0Á02). BMX, DCTPP1 and VGLL4 showed no differences in transcription between patients and healthy donors but were each found to be present at higher levels in B-ALL patient samples than HVs by ICC. BMX plays a crucial role in the Bruton's Tyrosine Kinase (BTK) pathway which is bound by the BTK inhibitor, ibrutinib, suggesting adult B-ALL would also be a worthy target patient group for future clinical trials. We have shown the utility of proto-array analysis of B-ALL patient sera, predominantly from young adults, to help characterise the B-ALL immunome and identified a new target patient population for existing small molecule therapy.

Identification of Genes Whose Expression Overlaps Age Boundaries and Correlates with Risk Groups in Paediatric and Adult Acute Myeloid Leukaemia

“…The cytoplasmic tyrosine kinase BMX was significantly different in its expression in paediatric AML between standard and low risk subgroups ( p = 6.36 × 10 −3 ), and in adults when comparing intermediate and good risk subgroups ( p = 5.74 × 10 −4 ). BMX has previously been found to be antigenic through sero-profiling of adult B-ALL [ 29 ] and is already used as a target for the small molecule therapy of mature B-cell malignancies [ 30 , 31 , 32 ] by virtue of its role in the B-cell receptor pathway. The current study suggests that the expression of BMX acts as a prognostic indicator in its own right, in adult AML patients (the perceived target of ibrutinib, for whom more than 80% express elevated levels of Bruton’s tyrosinase kinase (BTK) [ 33 ]), as well as in paediatric AML patients.…”

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

“…Extensive attempts have been made to define the genetic basis of ALL and to identify the many genetic lesions that contribute to leukaemogenesis. In this regard, it was interesting to note that B-ALL showed decreased heterogeneity compared with healthy volunteers by principal component analysis (PCA) in our study [34].…”

“…In summary, we have identified and characterised the expression of a number of tumour antigens that are overexpressed in adult B-ALL at disease presentation [22,34]. In doing so, we have found new targets for treatment, gained insights into the molecular mechanisms that underlie B-ALL at the earliest stages of disease and determined significant correlations between antigen expression and disease stage, and cytogenetic abnormalities.…”

“…These techniques examine patient samples through the analysis of RNA using RT-PCR [20], qPCR [22,29] and expression microarrays [30,31], urine [32], or peptides presented on MHC, using mass spectrometry [33], antibodies, i.e. serological analysis of recombinant cDNA expression libraries (SEREX) [21,24] and protein microarrays [34] and we have prioritised epitope specific T-cell responses using peptide-MHC arrays [27]. Other techniques are available, and as yet untested by our group including the next-generation sequencing (NGS) [35], RNA-sequencing (RNAseq), serological proteome analysis (SERPA), T-cell cloning and the combinatorial approach [32] and there are, of course, advantages and disadvantages to each, which primarily focus on costs, skills and equipment required.…”

“…We have also sero-profiled ten B-ALL samples [34], seven of which were pre-treatment/diagnosis, using 9000 proteins printed onto protein microarrays. We identified 19 antigens that were significant in their increased recognition by patients compared with eight age-and sex-matched healthy donor sera (p < 0.02) (Fig.…”