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.

Serum metabolome analysis by 1H-NMR reveals differences between chronic lymphocytic leukaemia molecular subgroups

“…Recently, it was reported that female CLL patients, who exhibit a apolipoprotein E4 (apoE4) genotype, have longer survival rates than non-apoE4 patients. 68 ApoE4 is the pro-apoptotic isoform of the apoE glycoprotein present in VLDL particles. Furthermore, they confirmed previous findings that poor-outcome CLL patients express higher levels of lipoprotein lipase mRNAFtranscript of the enzyme responsible for converting VLDL to LDL.…”

Somatic mutations in acute promyelocytic leukemia (APL) identified by exome sequencing

“…15 Finally, we identified several mutations affecting poorly characterized genes (for example, in TMEM56, NGLY1, GPR158, CYB5D2) without any known functions in blood cells, or mutations in genes with well-known functions that are most likely not relevant for hematological malignancy. For example, SEMG2 encodes a seminal protein and CUBN encodes the intrinsic factor, which is secreted by parietal cells in the gastric epithelium.…”

Reduced expression of the tumor suppressor PHLPP1 enhances the antiapoptotic B-cell receptor signal in chronic lymphocytic leukemia B-cells

“…[3][4][5] This kinase is also activated in response to many other microenvironmental stimuli that increase leukemic cell survival or induce proliferation, including CXCL12, CD40 ligand, IL-4, CpG oligonucleotides, lysophosphatidic acid, high-density lipoprotein particles and contact with bone marrow stromal cells. [6][7][8][9][10][11][12][13] In addition, increased basal Akt activity has been reported in some studies, suggesting that constitutive Akt signaling may contribute to the increased survival of the malignant lymphocytes. In line with this possibility, specific inhibition or downregulation of Akt has been shown to induce apoptosis in freshly isolated CLL cells.…”