BCR-ABL p210 b3a2 fusion peptide-Major Histocompatibility Complex (BCR-ABL b3a2 pMHC)

The BCR-ABL p210 b3a2 fusion peptide-Major Histocompatibility Complex (pMHC) is a highly specific neoantigen target found on the surface of leukemic cells in patients with Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (ALL). This complex is formed when the unique amino acid sequence at the b3a2 junction of the BCR-ABL1 fusion protein is intracellularly processed and presented by MHC class I molecules, such as HLA-A*02:01 (Bocchia et al., 1995, PMID: 8520004). Because this junctional epitope is entirely tumor-specific and absent in the normal human proteome, it serves as an ideal target for precision immunotherapies that aim to minimize off-target toxicity. Therapeutic strategies currently under investigation include TCR-engineered T-cells (TCR-T) and peptide-based vaccines designed to stimulate a robust T-cell mediated attack against the malignant clone (Cai et al., 2021, PMID: 33619314). While Tyrosine Kinase Inhibitors (TKIs) are the standard treatment for CML, they often fail to eliminate quiescent leukemic stem cells; targeting the surface-presented pMHC complex offers a complementary approach to achieve deep molecular responses and potential cure (Scheinberg et al., 2010, PMID: 20133973). Challenges for this target include the natural downregulation of MHC molecules by tumor cells to evade immune detection and the requirement for specific HLA haplotypes in the patient population.

Other names

BCR-ABL b3a2 neoantigen-MHC complexp210 b3a2 junctional peptide-HLA complexBCR-ABL fusion epitope-MHC complexBCR-ABL p210 b3a2 pMHC

Recognition of the specific fusion peptide-MHC complex by T-cell receptors (TCRs) or TCR-mimetic agents, which triggers a cytotoxic immune response and selective lysis of leukemic cells expressing the Philadelphia chromosome.