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

TitleGenetics of CD33 in Alzheimer's disease and acute myeloid leukemia.
Publication TypeJournal Article
Year of Publication2015
AuthorsMalik, 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
JournalHum Mol Genet
Volume24
Issue12
Pagination3557-70
Date Published2015 Jun 15
ISSN1460-2083
KeywordsAged, 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.

DOI10.1093/hmg/ddv092
Alternate JournalHum. Mol. Genet.
PubMed ID25762156
PubMed Central IDPMC4498153
Grant ListUL1 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