Splicing factor 3B subunit 1 (SF3B1) K700E-derived neoantigen QEVRTISAL presented by HLA-B*40:01 (SF3B1 K700E/HLA-B*40:01)

The Splicing factor 3B subunit 1 (SF3B1) K700E-derived neoantigen QEVRTISAL presented by HLA-B*40:01 is a tumor-specific peptide-MHC complex that serves as a therapeutic target for cancer immunotherapy, particularly in myeloid malignancies. SF3B1 is a critical component of the U2 small nuclear ribonucleoprotein (snRNP) complex involved in pre-mRNA splicing, and its K700E mutation is a frequent driver in Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) [1, 3]. This missense mutation replaces a lysine (K) with a glutamic acid (E) at position 700, which corresponds to the second position (P2) of the nonameric peptide QEVRTISAL. Because glutamic acid is a preferred anchor residue for the HLA-B*40:01 molecule, the mutation creates a high-affinity peptide-MHC complex that is naturally processed and presented on the surface of malignant cells, whereas the wild-type peptide (QKVRTISAL) binds poorly and is not presented [1, 6]. This differential presentation provides a therapeutic window for T-cell receptor (TCR)-engineered T-cell therapies to selectively target and lyse tumor cells while sparing healthy tissues [2, 5]. Preclinical studies have identified high-avidity TCRs, such as the D1.C24 clone, which demonstrate potent and specific cytotoxicity against SF3B1-mutated cells in both in vitro and in vivo models [1, 3]. As a shared neoantigen, this target is particularly valuable because the K700E mutation occurs in a significant percentage of patients with SF3B1-mutated MDS, offering a precision medicine approach for those carrying the HLA-B*40:01 allele [3, 9].

Other names

SF3B1 K700E neoepitopeQEVRTISAL-HLA-B*40:01 complexSF3B1 mutation-derived neoantigenSF3B1 K700E/HLA-B*40:01 pMHC

T-cell receptor (TCR) binding to the peptide-MHC complex, triggering cytotoxic T-lymphocyte (CTL) activation and tumor cell lysis.