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

Yeomans, Alison; Thirdborough, Stephen M.; Valle-Argos, Beatriz; Linley, Adam; Krysov, Sergey; Hidalgo, Marina Sánchez; Leonard, Elodie; Ishfaq, Muhammad; Wagner, Simon D.; Willis, Anne E.; Steele, Andrew J.; Stevenson, Freda K.; Forconi, Francesco; Coldwell, Mark J.; Packham, Graham

doi:10.1182/blood-2015-07-660969

Cited by 55 publications

(90 citation statements)

References 47 publications

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“…102 The BTK inhibitor ibrutinib can decrease levels of MYC protein in primary chronic lymphocytic leukemia cells exposed to IgM antibodies that stimulated BCR signaling. 103 In DLBCL, the best responses to ibrutinib occurred in patients with the ABC subtype, which can generate MYC and BCL2 from BCR signaling. 104 Bortezomib has been shown to decrease cell proliferation in BL cell lines, in part by decreasing expression of MYC protein.…”

Section: 89mentioning

confidence: 99%

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Sesques

Johnson

2017

Blood

134

116

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High-grade B-cell lymphomas (HGBLs) with MYC and BCL2 and/or BCL6 rearrangements, so-called “double-hit” lymphomas (HGBL-DH), are aggressive lymphomas that form a separate provisional entity in the 2016 revised World Health Organization Classification of Lymphoid Tumors. Fluorescence in situ hybridization (FISH) will be required to identify HGBL-DH and will reclassify a subset of diffuse large B-cell lymphomas (DLBCLs) and HGBLs with features intermediate between DLBCL and Burkitt lymphoma into this new category. Identifying patients with HGBL-DH is important because it may change clinical management. This poses a challenge for centers that may not be ready to handle the additional workload and financial burden associated with the increase in requests for FISH testing. Herein, we review the mechanisms of deregulation of these oncogenes. We identify the factors associated with a poor prognosis and those that can guide diagnostic testing. Restricting FISH analysis to the 10% of DLBCL patients who have a germinal center B-cell phenotype and coexpress MYC and BCL2 proteins would be cost-effective and would identify the subset of patients who are at highest risk of experiencing a relapse following conventional therapy. These patients may benefit from intensified chemotherapy regimens or, ideally, should enroll in clinical trials investigating novel regimens.

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Section: 89mentioning

confidence: 99%

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Sesques

Johnson

2017

Blood

134

116

View full text Add to dashboard Cite

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“…12, 13 In CLL signalling in the LN microenvironment promotes tumour cell proliferation 14 and two recent studies have shown the translational machinery is important in this context. 15, 16 Thus stimulation of PB CLL B-cells in vitro by either CD40L-expressing stromal cells or the B-cell receptor (BCR) promotes translation by stimulating eIF4F complex assembly or expression of eIF4G and eIF4A1. 15, 16 Following stimulation of the BCR, it has been shown that c-Myc protein levels are increased as a consequence of translation stimulation in CLL; 15 however, the full repertoire of the mRNAs (the translatome) that are controlled at this level has yet to be defined.…”

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confidence: 99%

A ribosome-related signature in peripheral blood CLL B cells is linked to reduced survival following treatment

et al. 2016

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We have used polysome profiling coupled to microarray analysis to examine the translatome of a panel of peripheral blood (PB) B cells isolated from 34 chronic lymphocytic leukaemia (CLL) patients. We have identified a ‘ribosome-related' signature in CLL patients with mRNAs encoding for ribosomal proteins and factors that modify ribosomal RNA, e.g. DKC1 (which encodes dyskerin, a pseudouridine synthase), showing reduced polysomal association and decreased expression of the corresponding proteins. Our data suggest a general impact of dyskerin dysregulation on the translational apparatus in CLL and importantly patients with low dyskerin levels have a significantly shorter period of overall survival following treatment. Thus, translational dysregulation of dyskerin could constitute a mechanism by which the CLL PB B cells acquire an aggressive phenotype and thus have a major role in oncogenesis.

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“…OPP-labeling was combined with staining with anti-CD19 and anti-CD5 antibodies to identify CLL cells, and scatter analysis was used to gate on viable cells [24]. OPP-labeling confirmed that PEITC inhibited both basal and anti-IgM-induced mRNA translation within the malignant clone (Figure 4C).…”

Section: Resultsmentioning

confidence: 94%

“…We investigated effects of PEITC on both basal (ie, in unstimulated cells treated with a control antibody) and anti-IgM-induced mRNA translation. mRNA translation was quantified at 24 hours, consistent with our previous study [24]. Anti-IgM signaling responses vary between samples and we selected a cohort of samples all of which were considered as signaling responsive based on our previous criteria [33].…”

Section: Resultsmentioning

confidence: 99%

PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2α phosphorylation in established cell lines and primary human leukemia cells

et al. 2016

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Increased mRNA translation drives carcinogenesis and is an attractive target for the development of new anti-cancer drugs. In this work, we investigated effects of phenethylisothiocyanate (PEITC), a phytochemical with chemopreventive and anti-cancer activity, on mRNA translation. PEITC rapidly inhibited global mRNA translation in human breast cancer-derived MCF7 cells and mouse embryonic fibroblasts (MEFs). In addition to the known inhibitory effects of PEITC on mTORC1 activity, we demonstrate that PEITC increased eIF2α phosphorylation. PEITC also increased formation of stress granules which are typically associated with eIF2α phosphorylation and accumulation of translationally stalled mRNAs. Analysis of genetically modified MEFs demonstrated that optimal inhibition of global mRNA translation by PEITC was dependent on eIF2α phosphorylation, but not mTORC1 inhibition. We extended this study into primary leukemic B cells derived from patients with chronic lymphocytic leukaemia (CLL). CLL cells were stimulated in vitro with anti-IgM to mimic binding of antigen, a major driver of this leukemia. In CLL cells, PEITC increased eIF2α phosphorylation, inhibited anti-IgM-induced mTORC1 activation and decreased both basal and anti-IgM-induced global mRNA translation. PEITC also inhibited transcription and translation of MYC mRNA and accumulation of the MYC oncoprotein, in anti-IgM-stimulated cells. Moreover, treatment of CLL cells with PEITC and the BTK kinase inhibitor ibrutinib decreased anti-IgM-induced translation and induced cell death to a greater extent than either agent alone. Therefore, PEITC can inhibit both global and mRNA specific translation (including MYC) via effects on multiple regulatory pathways. Inhibition of mRNA translation may contribute to the chemopreventive and anti-cancer effects of PEITC.

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

Abstract: Key Points BCR stimulation promotes mRNA translation in CLL cells, including of the oncoprotein, MYC, and is inhibited by ibrutinib or tamatinib. Differences in mechanisms of regulation of mRNA translation in CLL and normal blood B cells may highlight potential targets for therapy.

Cited by 55 publications

References 47 publications

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

A ribosome-related signature in peripheral blood CLL B cells is linked to reduced survival following treatment

PEITC-mediated inhibition of mRNA translation is associated with both inhibition of mTORC1 and increased eIF2α phosphorylation in established cell lines and primary human leukemia cells

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