Myeloid cell surface antigen CD33 isoform 2 (CD33-D2) (CD33-D2)

Myeloid cell surface antigen CD33 isoform 2 (CD33-D2), also known as CD33m, is a truncated splice variant of the CD33 receptor (Siglec-3) that lacks the V-set immunoglobulin-like domain (IgV) due to the skipping of exon 2 (UniProt P20248). This isoform retains the C2-set immunoglobulin-like domain (IgC or D2), the transmembrane region, and the intracellular signaling tail containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (PubMed: 23613520). Unlike the full-length CD33M isoform, CD33-D2 lacks the sialic acid-binding capacity required to trigger inhibitory signaling in myeloid cells and microglia (PubMed: 23995062). In the context of Alzheimer's disease, the CD33-D2 isoform is considered neuroprotective because its increased expression—often driven by the rs3865444 or rs12459419 genetic variants—correlates with enhanced microglial clearance of amyloid-beta plaques (PubMed: 30643240). Conversely, in acute myeloid leukemia (AML), the presence of this isoform can lead to resistance against therapies like gemtuzumab ozogamicin, which specifically target the IgV domain absent in CD33-D2 (PubMed: 28263186). Current therapeutic development focuses on antisense oligonucleotides (ASOs) and small molecules designed to modulate splicing to favor the production of this protective isoform for treating neurodegenerative conditions.

Other names

CD33mSiglec-3 isoform 2CD33 deltaE2p67 isoform 2CD33 IgC domain-only isoform

Modulation of alternative splicing to induce exon 2 skipping; Antibody-mediated receptor blockade or degradation