Identification of new MHC-restriction elements for presentation of the p210(BCR-ABL) fusion region to human cytotoxic T lymphocytes.

Chronic myelogenous leukemia (CML) is characterized by a t(9;22) translocation resulting in expression of BCR-ABL fusion oncoproteins which are unique to the leukemic cells, necessary for oncogenesis, and potentially immunogenic. We have previously shown that human dendritic cells transduced with an adeno-associated virus vector encoding the fusion region of the b3a2 splice variant (p210(b3a2)) of the BCR-ABL oncoprotein elicit specific T-cell responses in vitro. Two cytotoxic T lymphocyte (CTL) clones generated in this fashion displayed restriction with previously unreported HLA alleles. The first, T1/B9, was CD4(+) and restricted by DRB50101 (autologous) or DRB11101 (allogeneic). The minimum cytotoxic epitope (MCE) binding to DRB50101 for this clone was identified as FKQSSKALQ, overlapping the p210(b3a2) fusion point (boldface). The MCE of DRB11101 for this clone differed from DRB50101, but also included the fusion point. The clonality of CTL T1/B9 was verified by analyses of TCRalpha/beta chain usage and DNA sequence analyses. To our knowledge, this is the first description of a single clone recognizing both DRB50101 and DRB11101. The other CTL clone, T1/33, was CD8+ and recognized HLA-B3501 or B3503 complexed with an MCE, RPVASDFEP, derived from the c-abl sequence in proximity to the p210(b3a2) fusion point. K562 cells transfected with plasmids encoding HLA-DRA + B50101, B3501, or B3503 but not controls expressing DRA + DRB11501 were lysed by cognate CTL clones, confirming that DRB50101 and B3501/3 could present p210(b3a2) joining region epitopes via endogenous processing. The identification of three additional HLA alleles (DRB50101, B3501, and B3503) presenting the p210(b3a2) fusion-region antigen will broaden the application of vaccine strategies for targeting CML cells. The findings of single CTL clones cross-recognizing autologous (DRB50101 or B3501) and allogeneic (DRB11101 or B3503) HLA alleles presenting BCR-ABL fusion-region epitopes implies the potential separation of graft-versus-leukemia from graft-versus-host effects.