MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia

Cui, Bing; Chen, Liguang; Zhang, Suping; Mráz, Marek; Fecteau, Jessie F.; Yu, Jian; Ghia, Emanuela M.; Zhang, Ling; Bao, Lei; Rassenti, Laura Z.; Messer, Karen; Calin, George A.; Croce, Carlo M.; Kipps, Thomas J.

doi:10.1182/blood-2014-03-559690

Cited by 170 publications

(168 citation statements)

References 45 publications

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“…21,59 It also has been shown that BCR activation via a-IgM stimulation can induce cellular miR-155 expression in Ramos cells 70 and that transfection of miR-155 can enhance the sensitivity of CLL cells to BCR ligation. 61 These observations suggest a strong association between miR-155 and BCR activation. Given our results demonstrating that a-IgM stimulation increases exosome secretion from CLL cells, we examined expression levels of exosome microRNA following a-IgM treatment using quantitative real-time PCR.…”

Section: Levels Of Exosome Mir-150 and Mir-155 Increased On Bcr Activmentioning

confidence: 69%

“…Cellular expression of these microRNAs has previously been associated with CLL disease. 59,[61][62][63][64] Moreover, other differentially expressed microRNAs identified in the CLL exosome microRNA profile have been shown to be abnormally expressed and implicated in the development of other types of cancer. [65][66][67][68][69] We then confirmed the results of exosome microRNA profiling by quantitative real-time PCR and verified that levels of miR-150, miR-155, and miR-29a-c are significantly higher in circulating CLL exosomes compared with exosomes from healthy donors (P , .001 for all comparisons; Figure 6A).…”

Section: Characterization Of Plasma-derived Exosomes In Cllmentioning

confidence: 99%

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Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

Yeh¹,

Özer²,

Lehman³

et al. 2015

Blood

139

152

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Key Points• CLL exosomes exhibit a disease-relevant microRNA signature.• B-cell receptor signaling enhances exosome secretion in CLL that can be antagonized by ibrutinib.Multiple studies show that chronic lymphocytic leukemia (CLL) cells are heavily dependent on their microenvironment for survival. Communication between CLL cells and the microenvironment is mediated through direct cell contact, soluble factors, and extracellular vesicles. Exosomes are small particles enclosed with lipids, proteins, and small RNAs that can convey biological materials to surrounding cells. Our data herein demonstrate that CLL cells release significant amounts of exosomes in plasma that exhibit abundant CD37, CD9, and CD63 expression. Our work also pinpoints the regulation of B-cell receptor (BCR) signaling in the release of CLL exosomes: BCR activation by a-immunoglobulin (Ig)M induces exosome secretion, whereas BCR inactivation via ibrutinib impedes a-IgM-stimulated exosome release. Moreover, analysis of serial plasma samples collected from CLL patients on an ibrutinib clinical trial revealed that exosome plasma concentration was significantly decreased following ibrutinib therapy. Furthermore, microRNA (miR) profiling of plasma-derived exosomes identified a distinct exosome microRNA signature, including miR-29 family, miR-150, miR-155, and miR-223 that have been associated with CLL disease. Interestingly, expression of exosome miR-150 and miR-155 increases with BCR activation. In all, this study successfully characterized CLL exosomes, demonstrated the control of BCR signaling in the release of CLL exosomes, and uncovered a disease-relevant exosome microRNA profile. (Blood. 2015;125(21):3297-3305) IntroductionChronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the western world and remains incurable with current therapies. Understanding the different contributors to pathogenesis in CLL represents a path by which improved therapeutic options can be proposed. Although the pathogenesis of CLL for many years has been attributed to defective apoptosis of tumor cells, robust death is typically noted when these are removed from the body, suggesting a strong role of nurturing in the tumor microenvironment.1 In vivo, CLL cells reside in close contact with T lymphocytes, stromal cells, monocyte-derived nurse-like cells, follicular dendritic cells, and macrophages, collectively referred to as the "microenvironment." Interactions between these components result in CLL cell trafficking, survival, proliferation, and the increase of the apoptotic threshold, which may be partly dependent on direct physical cell-to-cell contact or mediated through soluble factors. This crosstalk between CLL and the microenvironment is bidirectional; thus, CLL cells are not only being supported by the microenvironment but also are capable of activating and signaling through the secretion of mediators that sustain and promote their survival advantage. In vitro models and gene expression profiles have identified important pathways for the...

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Section: Levels Of Exosome Mir-150 and Mir-155 Increased On Bcr Activmentioning

confidence: 69%

Section: Characterization Of Plasma-derived Exosomes In Cllmentioning

confidence: 99%

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

Yeh¹,

Özer²,

Lehman³

et al. 2015

Blood

139

152

View full text Add to dashboard Cite

show abstract

“…3,51 Clearly, there is a potential for microenvironmental factors to influence BCR signalling, and previous studies have shown that BAFF and CD40L promote sIgM-mediated signalling in CLL cells. 52 In those studies, regulation appeared to involve an indirect potentiation of intracellular signal transduction via microRNA-155-mediated suppression of the inhibitory phosphatase SHIP1. 52 By contrast, IL-4 appears to promote sIgM signalling, at least in part, via direct upregulation of IgM expression at the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…52 In those studies, regulation appeared to involve an indirect potentiation of intracellular signal transduction via microRNA-155-mediated suppression of the inhibitory phosphatase SHIP1. 52 By contrast, IL-4 appears to promote sIgM signalling, at least in part, via direct upregulation of IgM expression at the cell surface.…”

Section: Discussionmentioning

confidence: 99%

IL-4 enhances expression and function of surface IgM in CLL cells

Aguilar-Hernández

Blunt

Dobson

et al. 2016

Blood

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Key Points• IL-4 treatment augments sIgM expression and subsequent downstream signalling in a JAK3/STAT6 dependent manner within CLL samples.• IL-4 exposure partially opposes the activity of Bruton tyrosine kinase or PI3K inhibitors on sIgM-mediated signalling.Kinase inhibitors targeting the B-cell receptor (BCR) are now prominent in the treatment of chronic lymphocytic leukemia (CLL). We have focused here on interleukin 4 (IL-4), a cytokine that protects normal and malignant B cells from apoptosis and increases surface immunoglobulin M (sIgM) expression on murine splenic B cells. First, we have demonstrated that IL-4 treatment increased sIgM expression in vitro on peripheral blood B cells obtained from healthy individuals. In CLL, IL-4 target genes are overexpressed in cells purified from the lymph nodes of patients compared with cells derived from matched blood and bone marrow samples. As for normal B cells, IL-4 increased sIgM expression on CLL cells in vitro, especially in samples expressing unmutated V-genes. IL-4-induced sIgM expression was associated with increased receptor signalling activity, measured by anti-IgM-induced calcium mobilization, and with increased expression of CD79B messenger RNA and protein, and the "mature" glycoform of sIgM. Importantly, the ability of the BCR-associated kinase inhibitors idelalisib and ibrutinib, approved for treatment of CLL and other B-cell malignancies, to inhibit anti-IgM-induced signalling was reduced following IL-4 pretreatment in samples from the majority of patients. In contrast to stimulatory effects on sIgM, IL-4 decreased CXCR4 and CXCR5 expression; therefore, CLL cells, particularly within the progressive unmutated V-gene subset, may harness the ability of IL-4 to promote BCR signalling and B-cell retention within lymph nodes. Effects of IL-4 were mediated via JAK3/STAT6 and we propose a potential role for JAK inhibitors in combination with BCR kinase inhibitors for the treatment of CLL. (Blood. 2016;127(24):3015-3025)

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“…At that time it was identified as an oncogene called B-cell integration cluster (BIC) which induced B-cell leucosis in chickens (14). Further work demonstrated that transgenic mice overexpressing miR-155 developed lymphomas, and clinical studies found an association between miR-155 expression and bad prognosis in several human malignancies (15,16).…”

Section: Commentarymentioning

confidence: 99%

Cancer stem cell-associated microRNAs: searching for markers and targets in hepatocellular carcinoma

Hernández-Alcoceba

Fortes

2016

Transl. Gastroenterol. Hepatol.

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MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia

Cited by 170 publications

References 45 publications

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling

IL-4 enhances expression and function of surface IgM in CLL cells

Cancer stem cell-associated microRNAs: searching for markers and targets in hepatocellular carcinoma

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