Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia

Abstract

The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody. We seek to evaluate the extent to which CD33 genetics in AD and AML can inform one another and advance human disease therapy. We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA. Here, we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes from AML patients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419T allele decreases prototypic full-length CD33 expression by ∼ 25% and decreases the AD odds ratio by ∼ 0.10. These results suggest that CD33 antagonists may be useful in reducing AD risk. CD33 inhibitors may include humanized CD33 antibodies such as lintuzumab which was safe but ineffective in AML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as low as 10 ng/ml. Overall, we propose a model wherein a modest effect on RNA splicing is sufficient to mediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases

“…CD33 is expressed in the brain and on AML blasts and leukemic stem cells and has therefore been exploited therapeutically as a target for anti-leukemic therapy. 40 The CD33 rs3865444 and rs12459419 variants associated with lower WBC count and alternative splicing of exon 2, respectively, have been associated with both Alzheimer disease risk and AML treatment efficacy. 40 The exon 2 region of CD33 is important for sialic acid binding, microglial cell phagocytosis of beta-amyloid, and an epitope recognized by the antibody-targeted chemotherapy agent gemtuzumab ozogamicin.…”

CD33 in Alzheimer’s Disease – Biology, Pathogenesis, and Therapeutics: A Mini-Review

“…Notably, two CD33 antibodies, gemtuzumab ozogamicin (trade name Mylotarg) and lintuzumab, have been tested extensively in humans for treating acute myeloid leukemia (AML) and can effectively reduce cell surface CD33 expression in monocytes [35]. The humanized monoclonal antibody lintuzumab downregulated cell surface CD33 up to 50% in nondifferentiated U937 cells and up to 80% in PMA-differentiated U937 cells at a concentration as low as 10 ng/ mL [22]. This concentration is about 0.1% of the plasma concentration of AML patients treated with lintuzumab [22].…”

“…Since both gemtuzumab ozogamicin and lintuzumab are antibodies against the domain encoded by exon 2 [22], they will not recognize D2-CD33, which comprises 2-40% of total CD33 in the TCGA cohort. Individuals homozygous for the major allele of rs12459419 expressed 7.2% of their CD33 as D2-CD33; this portion increased to 17.4% in homozygous minor individuals [22]. Individuals carrying the minor allele of the SNP may be less responsive to treatment, in part because their cells produce more of the D2-CD33 variant.…”

“…CD33 expression is elevated in AD patients' brains, where it is thought to modulate microglial activation and inhibit Aβ clearance [16][17][18][19]. The capability of microglia for clearance of Aβ seems to be regulated by CD33 surface expression and alternative splicing, likely through D2 domain-dependent activation [15][16][17][18][19][20][21][22]. As such, interventions through small molecules or immunotherapy may represent the main strategies for treating AD.…”

Gemtuzumab ozogamicin for acute myeloid leukemia

“…by guest www.bloodjournal.org From Although some of the variability in CD33 expression by AML blasts relates to cytogenetic and mutational subtypes, much was unexplained until the recent demonstration that a germline CD33 single-nucleotide polymorphism, rs12459419, is associated with the expression of an alternatively spliced variant of CD33 lacking the GO-binding site (immunoglobulin V domain). 36,37 Essentially all available diagnostic antibodies target the same CD33 immunoglobulin V domain, so this single-nucleotide polymorphism defines whether AML blasts will appear to be CD33 1 or CD33…”