SPECIFIC BINDING OF LEUKEMIA ONCOGENE FUSION PROTEIN-PEPTIDES TO HLA CLASS-I MOLECULES

Many human leukemias are characterized by chromosomal translocations y ielding hybrid RNAs capable of encoding fusion chimeric proteins. The unique amino acid sequences found in these oncogenic fusion proteins r epresent true tumor-specific antigens that are potentially immunogenic . Although these leukemia-specific fusion proteins have an intracellul ar location, they might be recognized immunologically by T lymphocytes if peptides derived from the unique sequences are capable of presenta tion by the major histocompatibility complex (MHC) molecules on leukem ic cells. The ability of a series of synthetic peptides corresponding to the junctional sequences of chronic myelogenous leukemia (CML)-deri ved bcr-abl and acute promyelocytic leukemia (APL)-derived PML-RAR alp ha fusion proteins to bind to purified class I molecules was studied. A series of 152 peptides 8, 9, 10, and 11 amino acids in length, spann ing the b3a2 and b2a2 breakpoints for CML and PML-RAR alpha A and B br eakpoints for APL were analyzed for HLA A1, A2.1, A3.2, A11, A24, B7, B8, and B27 binding motifs. Twenty-one CML peptides and 4 APL peptides were predicted to be potential HLA class I binders. The peptides were tested for binding to appropriate purified HLA molecules in a competi tion radioimmunoassay. Four peptides derived from b3a2 CML breakpoint bound with high (<50 nmol/L) or intermediate (less than or equal to 50 0 nmol/L) affinity to HLA A3, A11, and B8. None of the CML b2a2 or PML -RAR alpha A or B junctional peptides showed affinity of this magnitud e for the HLA class I molecules tested. This is the first evidence tha t tumor-specific breakpoint peptides can bind human MHC class I molecu les and provides a rationale for developing a therapeutic vaccine stra tegy. (C) 1995 by The American Society of Hematology.