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Apolipoprotein E (APOE) Genotype as a Determinant of Survival in Women with Chronic Lymphocytic Leukemia.

Publication ,  Conference
Weinberg, JB; Volkheimer, AD; Mihovilovic, M; Jiang, N; Chen, Y; Moore, JO; Gockerman, JP; Diehl, LF; de Castro, CM; Rizzieri, DA; Levesque, MC ...
Published in: Blood
November 16, 2007

Survival of CLL cells requires sustained activation of the anti-apoptotic PI-3-kinase/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or anti-apoptotic. High density lipoprotein (HDL) particles are anti-apoptotic through sphingosine-1-phosphate receptor 3 (S1P3)-mediated activation of the PI-3-K/Akt pathway. We have noted that apoE4-very low density lipoprotein (VLDL) (but not apoE2- or apoE3-VLDL) particles increase apoptosis of endothelial cells by recruiting the phosphoinositol phosphatase SHIP-2 to the plasma membrane, thereby directly inhibiting the anti-apoptotic activity of HDL (DeKroon R, et al., Circ Res99:829–836, 2006). Since apoE4-VLDL increases apoptosis of certain cells, and since increased leukemia cell apoptosis favors longer survival in CLL, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. Of the 193 CLL patients (50 women and 133 men) studied, 29% had an APOE4 genotype. In the entire group, survival of men and women was not statistically different. However, women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients (median >25 yr vs. 14.0 yr; p = 0.02) (Figure).Figure FigureMen and women had the same time-to-treatment (treatment-free survival) irrespective of APOE genotype. VLDL is metabolized to LDL by the actions of LPL. Patients had shorter survival and time-to-treatment if their CLL cell lipoprotein lipase (LPL) mRNA levels were high (p = 0.002). In analyzing APOE genotype and LPL levels in the same patients, we demonstrated that APOE4 was a more important determinant of survival than was the LPL level (p = 0.0007). The beneficial effect of APOE4 in CLL survival is likely mediated through allele-specific influences of APOE4 on serum lipoproteins increasing leukemia cell apoptosis. The frequency of the APOE alleles in the CLL patient population was not significantly different than that of a control population (16 and 13%, respectively). APOE genotype therefore does not appear to affect susceptibility to CLL, but influences the clinical course of disease, particularly after therapy is initiated. In contrast, APOE genotype does influence susceptibility to other diseases, most notably Alzheimer’s disease in which APOE4 markedly increases risk. The beneficial impact of APOE4 in CLL and its deleterious impact on Alzheimer’s disease expression may relate to a common mechanism of APOE4 in enhancing apoptotic cell death. APOE genotyping of patients with CLL may provide important clinical prognostic information, particularly in women. Most importantly, the allele-specific influence of APOE on disease progression may provide important new insights into the mechanisms of disease and response to therapy, and lead to new agents for treatment.

Duke Scholars

Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 16, 2007

Volume

110

Issue

11

Start / End Page

3081 / 3081

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

Citation

APA
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Weinberg, J. B., Volkheimer, A. D., Mihovilovic, M., Jiang, N., Chen, Y., Moore, J. O., … Strittmatter, W. J. (2007). Apolipoprotein E (APOE) Genotype as a Determinant of Survival in Women with Chronic Lymphocytic Leukemia. In Blood (Vol. 110, pp. 3081–3081). American Society of Hematology. https://doi.org/10.1182/blood.v110.11.3081.3081
Weinberg, J Brice, Alicia D. Volkheimer, Mirta Mihovilovic, Ning Jiang, Youwei Chen, Joseph O. Moore, Jon P. Gockerman, et al. “Apolipoprotein E (APOE) Genotype as a Determinant of Survival in Women with Chronic Lymphocytic Leukemia.” In Blood, 110:3081–3081. American Society of Hematology, 2007. https://doi.org/10.1182/blood.v110.11.3081.3081.
Weinberg JB, Volkheimer AD, Mihovilovic M, Jiang N, Chen Y, Moore JO, et al. Apolipoprotein E (APOE) Genotype as a Determinant of Survival in Women with Chronic Lymphocytic Leukemia. In: Blood. American Society of Hematology; 2007. p. 3081–3081.
Weinberg, J. Brice, et al. “Apolipoprotein E (APOE) Genotype as a Determinant of Survival in Women with Chronic Lymphocytic Leukemia.Blood, vol. 110, no. 11, American Society of Hematology, 2007, pp. 3081–3081. Crossref, doi:10.1182/blood.v110.11.3081.3081.
Weinberg JB, Volkheimer AD, Mihovilovic M, Jiang N, Chen Y, Moore JO, Gockerman JP, Diehl LF, de Castro CM, Rizzieri DA, Levesque MC, DeKroon R, Strittmatter WJ. Apolipoprotein E (APOE) Genotype as a Determinant of Survival in Women with Chronic Lymphocytic Leukemia. Blood. American Society of Hematology; 2007. p. 3081–3081.

Published In

Blood

DOI

EISSN

1528-0020

ISSN

0006-4971

Publication Date

November 16, 2007

Volume

110

Issue

11

Start / End Page

3081 / 3081

Publisher

American Society of Hematology

Related Subject Headings

  • Immunology
  • 3213 Paediatrics
  • 3201 Cardiovascular medicine and haematology
  • 3101 Biochemistry and cell biology
  • 1114 Paediatrics and Reproductive Medicine
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology