Mechanisms of B-cell lymphoma pathogenesis

Küppers, Ralf

doi:10.1038/nrc1589

Cited by 782 publications

(705 citation statements)

References 139 publications

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“…In addition, Kaye et al (1993) have shown that this viral protein is essential for B-cell-transforming capacity of EBV. This is consistent with observations where LMP1 is expressed in lymphoproliferative diseases and B-cell lymphomas in immunocompromised patients (Horenstein et al, 1997;Ku¨ppers, 2005). LMP1 thus has been widely studied for its oncogenic properties (Eliopoulos and Young, 2001).…”

Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bsupporting

confidence: 90%

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Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

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Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response.

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Section: Ebv Lmp1 Regulates Tcl1 Through Mir-29bsupporting

confidence: 90%

“…The highly efficient process of B-cell transformation induced by Epstein-Barr virus (EBV) is due to a concerted function of its nine latent proteins (Ku¨ppers, 2005). The latent membrane protein 1 (LMP1) is one of the major effectors of this transformation (Kaye et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

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“…These malignancies frequently contain oncogenic IG translocations. Inactivating somatic mutations of TP53 correlate with IGH translocations in diffuse large B-cell lymphoma (DLBCL) and BL, as well as chemotherapy resistance, rapid disease progression and poor prognosis in patients with B lymphoid tumors (Kuppers, 2005;Cheung et al, 2009). Our analysis of mb1-cre:Tp53 flox/flox mice provides evidence that the somatic TP53 mutations found in DLBCL and BL may contribute to the development of these malignancies.…”

Section: Resultsmentioning

confidence: 76%

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

et al. 2011

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Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53-deficient (Tp53 À/À ) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multilineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53 flox/flox mice succumbed to lymphoid tumors containing Ig gene rearrangements and immunophenotypes characteristic of B cells from various developmental stages. Most mb1-cre: Tp53 flox/flox tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs.Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies.

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“…Most B‐cell tumors seem to be dependent on a continuous or tonic BCR signal for their proper growth (Kuppers, 2005). A recent study of murine BL cells showed, similar to our data, that BCR‐negative cells are less fit in a competitive growth assay (Varano et al , 2017).…”

Section: Discussionmentioning

confidence: 99%

“…Expression of, and signaling from, the pre‐BCR or BCR is also required for the continuous growth of several B‐cell lymphomas (Gauld et al , 2002; Kuppers, 2005; Lenz & Staudt, 2010; Stevenson et al , 2011). For instance, most B cells of chronic lymphocytic leukemia (B‐CLL) carry an auto‐aggregated BCR, which promotes continuous ITAM and PI3K signaling and is required for the expansion and survival of these tumor cells (Duhren‐von Minden et al , 2012).…”

Section: Introductionmentioning

confidence: 99%

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

Kläsener

Iype

et al. 2018

The EMBO Journal

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Expression of the B‐cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B‐cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine‐based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B‐cell co‐receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b), and the co‐receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igβ can be expressed on the B‐cell surface, where it is found in close proximity to CD19 and signals in an ITAM‐dependent manner. These data suggest that Igβ and CD19 are part of an alternative B‐cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells.

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Mechanisms of B-cell lymphoma pathogenesis

Cited by 782 publications

References 139 publications

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

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