CD86 regulates myeloma cell survival

Gavile, Catherine M.; Barwick, Benjamin G.; Newman, Scott; Neri, Paola; Nooka, Ajay K.; Lonial, Sagar; Lee, Kelvin P.; Boise, Lawrence H.

doi:10.1182/bloodadvances.2017011601

Cited by 21 publications

(28 citation statements)

References 42 publications

(34 reference statements)

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“…CD86, which is the cognate ligand for the prototypic T cell co-stimulatory molecule CD28, is expressed by myeloma cells and is required for their survival [148]. Since we have shown that CD28 itself is important in myeloma progression and survival [121,122,149], this CD28/CD86 axis may represent a possible mechanism by which cis-interactions in the myeloma cell microenvironment may facilitate survival and disease progression.…”

Section: Cd28: Bridging the Bmme And Intrinsic Survival Programs In Lmentioning

confidence: 83%

Targeting Multiple Myeloma through the Biology of Long-Lived Plasma Cells

Utley

Lipchick

Lee

et al. 2020

Cancers

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Multiple myeloma (MM) is a hematological malignancy of terminally differentiated bone marrow (BM) resident B lymphocytes known as plasma cells (PC). PC that reside in the bone marrow include a distinct population of long-lived plasma cells (LLPC) that have the capacity to live for very long periods of time (decades in the human population). LLPC biology is critical for understanding MM disease induction and progression because MM shares many of the same extrinsic and intrinsic survival programs as LLPC. Extrinsic survival signals required for LLPC survival include soluble factors and cellular partners in the bone marrow microenvironment. Intrinsic programs that enhance cellular fidelity are also required for LLPC survival including increased autophagy, metabolic fitness, the unfolded protein response (UPR), and enhanced responsiveness to endoplasmic reticulum (ER) stress. Targeting LLPC cell survival mechanisms have led to standard of care treatments for MM including proteasome inhibition (Bortezomib), steroids (Dexamethasone), and immunomodulatory drugs (Lenalidomide). MM patients that relapse often do so by circumventing LLPC survival pathways targeted by treatment. Understanding the mechanisms by which LLPC are able to survive can allow us insight into the treatment of MM, which allows for the enhancement of therapeutic strategies in MM both at diagnosis and upon patient relapse.

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Section: Cd28: Bridging the Bmme And Intrinsic Survival Programs In Lmentioning

confidence: 83%

Targeting Multiple Myeloma through the Biology of Long-Lived Plasma Cells

Utley

Lipchick

Lee

et al. 2020

Cancers

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“…Recent studies have shown that LLPCs primarily use FAO to generate ATP ( Lam et al, 2016 ). To determine if CD28 regulated LLPC metabolism, we first analyzed gene expression in three human CD28 + MM cell lines following CD28 knockdown (KD) ( Gavile et al, 2017 ), as CD28 activation in MM very closely mirrors what is seen in primary PCs ( Boise et al, 2014 ). Several Gene Ontology pathways directly associated with mitochondrial metabolism were significantly downregulated by CD28 KD, including mitochondrial electron transport and the tricarboxylic acid cycle ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…The murine PC line XXO responds to CD28 activation but has heterogeneous CD28 expression, so we began by flow-sorting into CD28 high and CD28 low populations ( Figure 5A ). Both expressed comparable levels of CD80 and CD86 ( Figure S3A ), which allows endogenous CD28 activation ( Gavile et al, 2017 ; Murray et al, 2014 ) and comparison of CD28 high versus CD28 low XXO metabolic profiles without exogenous CD28 activation. We first examined glycolysis by real-time measurement of the extracellular acidification rate (ECAR), an approach that has been established for T cells and LLPCs ( Lam et al, 2016 ; van der Windt et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival

et al. 2020

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SUMMARY Durable humoral immunity against epidemic infectious disease requires the survival of long-lived plasma cells (LLPCs). LLPC longevity is dependent on metabolic programs distinct from short-lived plasma cells (SLPCs); however, the mechanistic basis for this difference is unclear. We have previously shown that CD28, the prototypic T cell costimulatory receptor, is expressed on both LLPCs and SLPCs but is essential only for LLPC survival. Here we show that CD28 transduces pro-survival signaling specifically in LLPCs through differential SLP76 expression. CD28 signaling in LLPCs increased glucose uptake, mitochondrial mass/respiration, and reactive oxygen species (ROS) production. Unexpectedly, CD28-mediated regulation of mitochondrial respiration, NF-κB activation, and survival was ROS dependent. IRF4, a target of NF-κB, was upregulated by CD28 activation in LLPCs and decreased IRF4 levels correlated with decreased glucose uptake, mitochondrial mass, ROS, and CD28-mediated survival. Altogether, these data demonstrate that CD28 signaling induces a ROS-dependent metabolic program required for LLPC survival.

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“…This process involves K + channels, putatively explaining the relationship among these two minerals and CD86. The PI3k-akt signalling pathway is activated after CD86 protein binds to the CD86 receptor in an antigen-presenting cell, leading to downregulation of integrins, components of the ECM 34 .…”

Section: Discussionmentioning

confidence: 99%

Genetic regulators of mineral amount in Nelore cattle muscle predicted by a new co-expression and regulatory impact factor approach

Afonso

Fortes

Reverter

et al. 2020

Sci Rep

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Mineral contents in bovine muscle can affect meat quality, growth, health, and reproductive traits. to better understand the genetic basis of this phenotype in nelore (Bos indicus) cattle, we analysed genome-wide mRNA and miRNA expression data from 114 muscle samples. The analysis implemented a new application for two complementary algorithms: the partial correlation and information theory (pcit) and the regulatory impact factor (Rif), in which we included the estimated genomic breeding values (GeBVs) for the phenotypes additionally to the expression levels, originally proposed for these methods. We used PCIT to determine putative regulatory relationships based on significant associations between gene expression and GeBVs for each mineral amount. then, Rif was adopted to determine the regulatory impact of genes and miRnAs expression over the GeBVs for the mineral amounts. We also investigated over-represented pathways, as well as pieces of evidences from previous studies carried in the same population and in the literature, to determine regulatory genes for the mineral amounts. for example, NOX1 expression level was positively correlated to Zinc and has been described as Zinc-regulated in humans. Based on our approach, we were able to identify genes, miRnAs and pathways not yet described as underlying mineral amount. the results support the hypothesis that extracellular matrix interactions are the core regulator of mineral amount in muscle cells. putative regulators described here add information to this hypothesis, expanding the knowledge on molecular relationships between gene expression and minerals. Besides nutritional quality, mineral amount affects meat quality in many ways. For example, the tenderization process of the skeletal muscle is driven by the action of the calcium-dependent protease calpain 1-4. Minerals also affect reproduction, as copper, zinc, selenium and manganese supplementation improves pregnancy rate 5 ; as well as health and growth performance 6,7 in beef cattle. Mineral homeostasis regulation partially depends on genetic factors, among others 8. Thus, understanding the genetic aspects linked to mineral amount in bovine muscle can

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CD86 regulates myeloma cell survival

Cited by 21 publications

References 42 publications

Targeting Multiple Myeloma through the Biology of Long-Lived Plasma Cells

Targeting Multiple Myeloma through the Biology of Long-Lived Plasma Cells

CD28 Regulates Metabolic Fitness for Long-Lived Plasma Cell Survival

Genetic regulators of mineral amount in Nelore cattle muscle predicted by a new co-expression and regulatory impact factor approach

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