Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination

Park, Hye Young; Go, Heounjeong; Song, Ha Rim; Kim, Suhyeon; Ha, Geun-Hyoung; Jeon, Yoon Kyung; Kim, Ji Eun; Lee, Ho; Cho, Hyeseong; Kang, Ho Chul; Chung, Hee Yong; Kim, Chul Woo; Chung, Doo Hyun; Lee, Chang Woo

doi:10.1172/jci75667

Cited by 47 publications

(91 citation statements)

References 29 publications

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“…A similar mechanism might apply to cHL, which is characterized by constitutive activation of NF-ĸB [35]. PELI1 was shown to promote lymphomagenesis by K63 ubiquitination of BCL6, which resulted in enhanced BCL6 levels [36]. BCL6 protein expression is often negative in cHL [38], which is in line with low PELI1 and high miR-21-5p levels as observed in our study.…”

Section: Discussionsupporting

confidence: 88%

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

Yuan

Niu²,

Nolte

et al. 2018

Cell Physiol Biochem

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Background/Aims: Classical Hodgkin lymphoma (cHL) is among the most frequent lymphoma subtypes. The tumor cells originate from crippled germinal center (GC)-B cells that escaped from apoptosis. MicroRNAs (miRNAs) play important roles in B-cell maturation and aberrant expression of miRNAs contributes to the pathogenesis of cHL. Our aim was to identify oncogenic miRNAs relevant for growth of cHL using a high-throughput screening approach. Methods: A lentiviral pool of 63 miRNA inhibition constructs was used to identify miRNAs essential to cell growth in three cHL cell lines in duplicate. As a negative control we also infected cHL cell lines with a lentiviral barcoded empty vector pool consisting of 222 constructs. The abundance of individual constructs was followed over time by a next generation sequencing approach. The effect on growth was confirmed using individual GFP competition assays and on apoptosis using Annexin-V staining. Our previously published Argonaute 2 (Ago2) immunoprecipitation (IP) data were used to identify target genes relevant for cell growth / apoptosis. Luciferase assays and western blotting were performed to confirm targeting by miRNAs. Results: Four miRNA inhibition constructs, i.e. miR-449a-5p, miR-625-5p, let-7f-2-3p and miR-21-5p, showed a significant decrease in abundance in at least 4 of 6 infections. In contrast, none of the empty vector constructs showed a significant decrease in abundance in 3 or more of the 6 infections. The most abundantly expressed miRNA, i.e. miR-21-5p, showed significantly higher expression levels in cHL compared to GC-B cells. GFP competition assays confirmed the negative effect of miR-21-5p inhibition on HL cell growth. Annexin-V staining of cells infected with miR-21-5p inhibitor indicated a significant increase in apoptosis at day 7 and 9 after viral infection, consistent with the decrease in growth. Four miR-21-5p cell growth- and apoptosis-associated targets were AGO2-IP enriched in cHL cell lines and showed a significant decrease in expression in cHL cell lines in comparison to normal GC-B cells. For the two most abundantly expressed, i.e. BTG2 and PELI1, we confirmed targeting by miR-21-5p using luciferase assays and for PELI1 we also confirmed this at the protein level by western blotting. Conclusion: Using a miRNA loss-of-function high-throughput screen we identified four miRNAs with oncogenic effects in cHL and validated the results for the in cHL abundantly expressed miR-21-5p. MiR-21-5p is upregulated in cHL compared to GC-B cells and protects cHL cells from apoptosis possibly via targeting BTG2 and PELI1.

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Section: Discussionsupporting

confidence: 88%

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

Yuan

Niu²,

Nolte

et al. 2018

Cell Physiol Biochem

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“…PELI1 encodes the E3 ubiquitin ligase, Pellino1, which stabilizes BCL6 via K63 polyubiquitination and promotes B-cell lymphomagenesis in a murine model. 47 As in PCNSL, one PTL had a deletion proximal to BCL6 that removed the transcriptional start side and first 5 exons of LPP (supplemental Figure 4C). ETV6.…”

Section: Chromosomal Rearrangements In Ptlmentioning

confidence: 95%

“…In addition, BCL6 was deregulated by mutations of MEF2B, chromosomal translocations of BCL6 with immunoglobulin or nonimmunoglobulin regulatory elements, and a novel translocation of PELI1, which encodes an E3 ligase that stabilizes the BCL6 protein. 47 Unique combinations of structural alterations in discrete LBCL subtypes By comparing the comprehensive molecular signatures of PTL and PCNSL with those of systemic DLBCL and PMBLs, we identified unique combinations of genetic features in discrete LBCL subtypes ( Figure 7). For example, PCNSLs, PTLs, and PMBLs exhibit frequent genetic alterations and overexpression of the PD-1 ligands, whereas DLBCLs rarely have these features.…”

Section: Multiple Genetic Bases Of Target and Pathway Deregulationmentioning

confidence: 99%

Targetable genetic features of primary testicular and primary central nervous system lymphomas

Chapuy

Roemer

Stewart

et al. 2016

Blood

479

450

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“…This leads to a T-cell-intrinsic increase in Tfh differentiation, large numbers of germinal centers, and increased serum antibodies of various IgG isotypes, among other defects 98 . Bcl6 is regulated by two other E3 ligases in diffuse large B cell lymphomas (DLBCLs) 99,100 . Pellino1 E3 ligase (PELI1) directs K63 (non-degradative) chains on Bcl6 leading to Bcl6 stabilization in transgenic mice overexpressing human PELI1 99 .…”

Section: Tfh Cellsmentioning

confidence: 99%

“…Bcl6 is regulated by two other E3 ligases in diffuse large B cell lymphomas (DLBCLs) 99,100 . Pellino1 E3 ligase (PELI1) directs K63 (non-degradative) chains on Bcl6 leading to Bcl6 stabilization in transgenic mice overexpressing human PELI1 99 . Furthermore, in these lymphoma cell lines, another E3 ligase, FBXO11, that normally marks Bcl6 for degradation, is found to undergo loss of function mutations 100 .…”

Section: Tfh Cellsmentioning

confidence: 99%

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function

Layman

Oliver

2016

The Journal of Immunology

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The human body is exposed to potentially pathogenic microorganisms at barrier sites such as the skin, lungs, and GI tract. To mount an effective response against these pathogens, the immune system must recruit the right cells with effector responses that are appropriate for the task at hand. Several types of CD4+ T cells can be recruited, including T helper cells known as Th1, Th2, and Th17, T follicular helper (Tfh) cells, and regulatory T cells (Tregs). These cells help to maintain normal immune homeostasis in the face of constantly changing microbes in the environment. As these cells differentiate from a common progenitor, the composition of their intracellular milieu of proteins changes to appropriately guide their effector function. One underappreciated process that impacts both levels and functions of effector fate-determining factors is ubiquitylation. This review will detail our current understanding of how ubiquitylation regulates CD4 T cell effector identity and function.

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Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination

Cited by 47 publications

References 29 publications

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

MicroRNA High Throughput Loss-of-Function Screening Reveals an Oncogenic Role for miR-21-5p in Hodgkin Lymphoma

Targetable genetic features of primary testicular and primary central nervous system lymphomas

Ubiquitin Ligases and Deubiquitinating Enzymes in CD4+ T Cell Effector Fate Choice and Function

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