Surface IgM stimulation induces MEK1/2-dependent MYC expression in chronic lymphocytic leukemia cells

Krysov, Sergey; Dias, Samantha; Paterson, Alex; Mockridge, C. Ian; Potter, Kathleen; Smith, Kelly-Ann; Ashton‐Key, Margaret; Stevenson, Freda K.; Packham, Graham

doi:10.1182/blood-2011-07-370403

Cited by 88 publications

(111 citation statements)

References 47 publications

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“…Consistent with previous studies demonstrating transcriptional increases, 11,17 anti-IgM increased the total amount of MYC mRNA detected in all fractions (compare first 2 bars in Figure 5A). There was also a clear increase in the amount of MYC mRNA present in polysomeassociated fractions, demonstrating that anti-IgM also increased MYC mRNA translation.…”

Section: Increased Mrna Translation Contributes To Increased Myc Exprsupporting

confidence: 80%

“…1 In addition to analyzing global mRNA translation, we also showed for the first time that MYC is a target for translational regulation in CLL after sIgM stimulation. We confirmed induction of MYC mRNA after sIgM stimulation 11,17 but also showed that increased mRNA translation contributed to induction of MYC protein. Interestingly, in addition to being translationally regulated, MYC may also play a role in upregulation of translation as part of a positive feedback loop.…”

Section: Increased Mrna Translation Contributes To Increased Myc Exprsupporting

confidence: 68%

“…Regulation of the UPR and MYC is consistent with our previous reports demonstrating induction of a partial UPR and MYC in CLL cells after sIgM stimulation in vitro, and in CLL cells in LN. 17,26 However, an important new finding was the particularly strong regulation of genes associated with mRNA translation. Because network analysis suggested a prominent role for increased mRNA translation after engagement of the BCR of CLL cells in vivo, we next investigated its potential regulation by anti-IgM in vitro.…”

Section: Org Frommentioning

confidence: 99%

“…Moreover, responses to bead-bound anti-IgD were clearly reduced compared with anti-IgM, consistent with our previous study demonstrating that although most CLL samples retain initial sIgD signaling responsiveness, anti-IgD fails to effectively induce MYC expression. 17 Further studies are required to probe the relationship between increased mRNA translation and other sIgM signaling responses, but increased mRNA translation is likely to be part of a constellation of responses coregulated downstream of sIgM in signal-responsive samples and sensitive to signal strength. 1 In addition to analyzing global mRNA translation, we also showed for the first time that MYC is a target for translational regulation in CLL after sIgM stimulation.…”

Section: Increased Mrna Translation Contributes To Increased Myc Exprmentioning

confidence: 99%

“…13,14 MYC RNA has a highly structured 59-untranslated region and is one of a family of malignancyassociated mRNAs for which translation is tightly dependent on eIF activity. 15,16 In our previous studies, we demonstrated that MYC protein was induced after stimulation of sIgM of CLL cells in vitro and that MYC is highly expressed in proliferation centers in CLL lymph nodes (LNs), 17 which are presumed to be the major sites of antigeninduced cell division in vivo. 18 Therefore, we hypothesized that MYC may be an important target for translational regulation in CLL.…”

Section: Introductionmentioning

confidence: 99%

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Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation

Yeomans

Thirdborough

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et al. 2016

Blood

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Section: Increased Mrna Translation Contributes To Increased Myc Exprsupporting

confidence: 80%

Section: Increased Mrna Translation Contributes To Increased Myc Exprsupporting

confidence: 68%

Section: Org Frommentioning

confidence: 99%

Section: Increased Mrna Translation Contributes To Increased Myc Exprmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation

Yeomans

Thirdborough

Valle-Argos

et al. 2016

Blood

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miR‐125b Is an Adhesion‐Regulated microRNA that Protects Mesenchymal Stem Cells from Anoikis

Cohen

Chen

2012

STEM CELLS

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Mesenchymal stem cells (MSCs) have the capacity for multilineage differentiation and are being explored as a source for stem cell-based therapies. Previous studies have shown that adhesion to extracellular matrix plays a critical role in guiding MSC differentiation to distinct lineages. Here we conducted a focused screen of microRNAs to reveal one microRNA, miR-125b, whose expression changes as a function of cell adhesion. miR-125b expression was upregulated by limiting cell-matrix adhesion using micropatterned substrates, knocking down beta5 integrin, or placing cells in suspension culture. Interestingly, we noted that suspending hMSCs did not induce substantial apoptosis (anoikis) as is typically observed in adherent cells. Although miR-125b appeared to have some effects of on hMSC differentiation, we demonstrated a striking role for miR-125b in protecting hMSCs from anoikis. Knockdown of miR-125b increased anoikis while expressing a mimic protected cells. Mechanistic studies demonstrated that miR-125b protected against anoikis by increasing ERK phosphorylation and by suppressing p53. Lastly, we found that miR-125b expression is quite limited in endothelial cells and MEFs; the rapid anoikis normally observed in these cells is antagonized by expressing a miR-125b mimic; and induced pluripotent stem (iPS) cells generated from the MEFs led to upregulated miR-125b expression. Together, these observations demonstrate a novel link between cell-matrix adhesion, miR-125b expression, and a stem-cell specific survival program triggered in adhesion-limited contexts such as might occur in early development and wound healing.

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The CLL Cell Microenvironment

Burger

2013

Advances in Experimental Medicine and Biology

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Cross talk between CLL cells and accessory stromal cells in specialized tissue microenvironments, such as the secondary lymphoid organs, favors CLL progression by promoting malignant B cell growth and drug resistance. Disrupting the cross talk between CLL cells and their milieu is an attractive, novel strategy for treating CLL patients. This chapter summarizes current knowledge about cellular and molecular interactions between CLL cells and their supportive tissue microenvironment and the therapeutic targets that are emerging, focusing on the CXCR4-CXCL12 axis and small molecule inhibitors that are targeting the B cell receptor-associated kinases SYK, BTK, and PI3Kδ. Clinically relevant aspects of these new therapeutics will be discussed, along with an outlook into future biologically oriented therapeutic strategies. The rapid progress in dissecting the CLL microenvironment and the promising early results of these new targeted treatments in CLL indicate that CLL has become a role model for microenvironment-dependent cancers.

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Surface IgM stimulation induces MEK1/2-dependent MYC expression in chronic lymphocytic leukemia cells

Cited by 88 publications

References 47 publications

Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation

Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation

miR‐125b Is an Adhesion‐Regulated microRNA that Protects Mesenchymal Stem Cells from Anoikis

The CLL Cell Microenvironment

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