Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia.
Title | Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Malik, M, Chiles, J, Xi, HS, Medway, C, Simpson, J, Potluri, S, Howard, D, Liang, Y, Paumi, CM, Mukherjee, S, Crane, P, Younkin, S, Fardo, DW, Estus, S |
Journal | Hum Mol Genet |
Volume | 24 |
Issue | 12 |
Pagination | 3557-70 |
Date Published | 2015 Jun 15 |
ISSN | 1460-2083 |
Keywords | Aged, Aged, 80 and over, Alleles, Alternative Splicing, Alzheimer Disease, Antibodies, Monoclonal, Humanized, Cell Line, Exons, Female, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Introns, Leukemia, Myeloid, Acute, Male, Polymorphism, Single Nucleotide, RNA Stability, RNA, Messenger, Sialic Acid Binding Ig-like Lectin 3 |
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. |
DOI | 10.1093/hmg/ddv092 |
Alternate Journal | Hum. Mol. Genet. |
PubMed ID | 25762156 |
PubMed Central ID | PMC4498153 |
Grant List | UL1 TR000117 / TR / NCATS NIH HHS / United States U01-AG032984 / AG / NIA NIH HHS / United States K25 AG043546 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States UL1 TR001108 / TR / NCATS NIH HHS / United States R01 AG045775 / AG / NIA NIH HHS / United States P01 AG030128 / AG / NIA NIH HHS / United States KL2 TR000116 / TR / NCATS NIH HHS / United States P01-AGO30128 / / PHS HHS / United States P30-AG028383 / AG / NIA NIH HHS / United States K25-AG043546 / AG / NIA NIH HHS / United States R01-AG045775 / AG / NIA NIH HHS / United States D43 TW000013 / TW / FIC NIH HHS / United States P30 AG028383 / AG / NIA NIH HHS / United States R25-GM093044 / GM / NIGMS NIH HHS / United States |