Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

Weinberg, J. Brice; Volkheimer, Alicia D.; Mihovilovic, Mirta; Jiang, Ning; Chen, Y; Bond, Karen M.; Moore, Joseph O.; Gockerman, Jon P.; Diehl, Louis F.; Castro, Carlos M. de; Rizzieri, David A.; Levesque, Marc C.; DeKroon, Robert M.; Strittmatter, Warren J.

doi:10.1038/leu.2008.241

Cited by 13 publications

(12 citation statements)

References 29 publications

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“…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.…”

Section: Classification Methodsmentioning

confidence: 99%

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

et al. 2010

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Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a 1 H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n ¼ 29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n ¼ 9). Differences in metabolic profiles between unmutated (UM-IGHV; n ¼ 10) and mutated IGHV (M-IGHV; n ¼ 19) patients were determined using partial least square discriminatory analysis (PLS-DA; R 2 ¼ 0.74, Q 2 ¼ 0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with diseaserelated metabolic profiles. Our results highlight the usefulness of 1 H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.

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Section: Classification Methodsmentioning

confidence: 99%

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

et al. 2010

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“…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.…”

Section: Letters To the Editormentioning

confidence: 99%

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

et al. 2011

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tumor-bearing mice, when compared with normal control nonirradiated mice (Figures 2c and d). Furthermore, exogenous rmHMGB1 (recombinant mouse HMGB1) showed its capacity to upregulate the IL6 and miR-21 expression level in a TLR4-dependent manner (Figure 2e). These data indicate the possible important role of HMGB1/TLR4/IL6-miR-21 pathway in radiation-induced carcinogenesis.Our data presented here may provide a novel possible mechanism for split-dose radiation-induced thymic lymphomas. As shown in Figure 2f, split-dose irradiation may injure the thymus cells, inducing apoptosis and necrosis, and releasing many danger-and death-related signals like HMGB1. This in turn may activate TLR4 and elevate the pro-tumor cytokines IL6 and miR-21, together with important factors like MMP9 and miR-155, to induce carcinogenesis. To the best of our knowledge, this is the first report describing a role for TLR4 in radiation-induced thymic lymphoma in vivo. This work therefore provides some novel experimental evidence about potential therapeutic targets for the prevention and treatment of radiationinduced carcinogenesis.

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“…[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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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The PI3K/Akt pathway is activated in response to various microenvironmental stimuli that regulate the survival and proliferation of chronic lymphocytic leukemia (CLL) B-cells, including triggering of the B-cell receptor (BCR). Although this pathway is frequently targeted in cancer, no significant alterations have yet been identified in CLL. We now show that the phosphatase PH domain leucin-rich repeat protein phosphatase (PHLPP1), a recently identified tumor suppressor and negative regulator of the Akt kinase, is absent or expressed at substantially reduced levels in CLL B-cells. To determine what the consequences of PHLPP1 loss on BCR signaling are, we downregulated or re-expressed PHLPP1 in lymphoma cell lines and primary CLL B-cells, respectively. Downregulation of PHLPP1 increased BCR-induced phosphorylation and activation of the Akt, GSK3 and ERK kinases, whereas re-expression had the opposite effect. Importantly, re-expression of PHLPP1 in primary CLL cells prevented upregulation of Mcl-1 and inhibited the increase in leukemic cell viability induced by sustained BCR engagement. Enforced expression of PHLPP1 also affected the response to other microenvironmental stimuli, particularly in terms of ERK phosphorylation. Collectively, these data show that CLL cells lack an important negative regulator of the Akt and ERK pathways, which could confer them a growth advantage by facilitating the propagation of crucial microenvironment-derived stimuli.

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Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia

Cited by 13 publications

References 29 publications

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

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

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

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

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