title: Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia.
abstract: Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.
authors.affiliation: Department of Medicine, Duke University and VA Medical Centers, Durham, NC 27705, USA. brice@duke.edu
authors.forename: J B
authors.initials: JB
authors.lastname: Weinberg
authors.forename: A D
authors.initials: AD
authors.lastname: Volkheimer
authors.forename: M
authors.initials: M
authors.lastname: Mihovilovic
authors.forename: N
authors.initials: N
authors.lastname: Jiang
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Bond
authors.forename: J O
authors.initials: JO
authors.lastname: Moore
authors.forename: J P
authors.initials: JP
authors.lastname: Gockerman
authors.forename: L F
authors.initials: LF
authors.lastname: Diehl
authors.forename: C M
authors.initials: CM
authors.lastname: de Castro
authors.forename: D A
authors.initials: DA
authors.lastname: Rizzieri
authors.forename: M C
authors.initials: MC
authors.lastname: Levesque
authors.forename: R
authors.initials: R
authors.lastname: Dekroon
authors.forename: W J
authors.initials: WJ
authors.lastname: Strittmatter
mesh_terms: D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D015243:Cholesterol, VLDL / Q000097:blood; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D012307:Risk Factors; D017678:Sex Distribution; D016019:Survival Analysis
chemical_list: D053327:Apolipoprotein E4; D015243:Cholesterol, VLDL; D008071:Lipoprotein Lipase