A BCR-ABL Oncoprotein p210b2a2 Fusion Region Sequence Is Recognized by HLA-DR2a Restricted Cytotoxic T Lymphocytes and Presented by HLA-DR Matched Cells Transfected With an Iib2a2 Construct

Abstract

Peptides corresponding to the fusion site in 210 kD BCR-ABL protein b3a2 (p210b3a2) were previously shown to bind to several HLA class I and II alleles. We have found that b3a2 peptide-specific CD4-positive T-helper cells were able to recognize p210b3a2-positive chronic myelogenous leukemia (CML) blasts in a DR4 restricted manner. Until now, there were no reports of b2a2 breakpoint-specific human T-cell responses. Here we show that repetitive stimulation of T lymphocytes with a 17mer peptide covering the fusion region in p210b2a2 also leads to specific T-cell responses. CD4 and CD4/CD8 double-positive clones obtained from a b2a2 peptide-specific cell line were cytotoxic and proliferative in an HLA-DR2a (DRB5*0101) restricted fashion. Autologous Epstein-Barr virus (EBV) transformed cells, expressing BCR-ABLb2a2 on transfection, and allogeneic HLA-DR matched p210b2a2-positive cells from CML patients were, however, not lysed. BCR-ABL peptide-specific T-cell clones did respond to autologous EBV cells transfected with invariant chain (li) cDNA in which the HLA class II–associated invariant chain peptide (CLIP) was replaced by a BCR-ABL b2a2 fusion oligonucleotide sequence, illustrating the potential of these T cells to recognize an endogenous BCR-ABLb2a2ligand.

Expression of co‐stimulatory and adhesion molecules and chemokine or apoptosis receptors on acute myeloid leukaemia: high CD40 and CD11a expression correlates with poor prognosis

“…In patients with haematological diseases, the presence of similar autologous T‐ or natural killer (NK)‐cell mediated anti‐tumour responses has not been consistently demonstrated. In patients with CML and chronic lymphoid leukaemia (CLL), proliferative and cytotoxic T‐cell responses have been observed against the bcr–abl fusion product and against modified CLL cells respectively (Bocchia et al , 1995; Ten Bosch et al , 1995, 1999; Kato et al , 1998; Yasukawa et al , 1998; Yotnda et al , 1998; Buhmann et al , 1999; Chu et al , 2000). In addition, autologous anti‐leukaemic T‐cell or NK cell responses have been generated in vitro against hairy cell leukaemia (HCL) (van de Corput et al , 1999), acute lymphoblastic leukaemia (ALL) (Montagna et al , 1995; Cardoso et al , 1997) and acute myeloid leukaemia (AML) (Archimbaud et al , 1992a; Charbonnier et al , 1999; Choudhury et al , 1999), although a clear immunosurveillance effect has never been demonstrated.…”

Leukemia‐associated antigens as target structures for a specific immunotherapy in chronic myeloid leukemia

“…Over 95% CML patients express the fusion product BCR-ABL on their tumor cells that could induce specific T cell responses (4). In last years, several peptides of the BCR-ABL fusion proteins were characterized (4,(21)(22)(23). Recently, Kessler et al and Volpe et al described novel BCR-ABL derived peptides (7,24).…”

Quantitative approaches to computational vaccinology

“…For MHC binding we have used a number of alternative measures of binding affinity, which are currently in common currency. These include radiolabelled 16 , 17 , 18 and fluorescent 19 , 20 , 21 IC 50 values, BL 50 22 , 23 , 24 (half maximal binding level calculated from a mean fluorescence intensity MFI of MHC‐expressing RMA‐S cells) and SC 50 25 , 26 , 27 (the concentration inducing half of the maximal up‐regulating effect calculated in a peptide‐binding stabilization assay), and half‐lives 6 , 28 , 29…”