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Synergy between PI3K Signaling and MYC in Burkitt Lymphomagenesis

ABSTRACT: In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE35219 | GEO | 2012/08/14

SECONDARY ACCESSION(S): PRJNA150649

REPOSITORIES: GEO

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Synergy between PI3K Signaling and MYC in Burkitt Lymphomagenesis

Project description:In Burkitt lymphoma (BL), an aggressive germinal-center (GC) derived non-Hodgkin B-cell lymphoma characterized by MYC translocations as early transforming event, the apoptotic properties of MYC must have been overcome by pro-survival signals. Whereas activation of the pro-survival factor NFkappaB is not eminent in BL, PI3K signalling, which mediates B cell receptor associated survival signals in mature B cells, might be the cooperating event. Here we prove this hypothesis by the generation of BL in mice upon concordant expression of MYC and activation of PI3K in GC B cells. Unlike existing murine BL-like models, our tumour model fully phenocopies primary human BL and reflects the complexity of the disease with regard to histological appearance, surface marker expression, and characteristic gene expression profiles. Like in human BL, tumour monoclonality indicated a multistep pathogenesis underlining MYC and PI3K as predisposing events that invariably lead to GC-derived BL formation. In accordance, copy number alteration analysis revealed genomic regions involved in BL pathogenesis. All samples were obtained from murine lymphomas (Cgamma1-cre; R26StopFLMYC;R26StopFLP110* animals). Cells used for microarray analysis were sorted reporter positive cells. Tumour cells were compared to a matched germline DANN sample to identify acquired aberrations.

2012-08-13 | E-GEOD-35219 | biostudies-arrayexpress

Nuclear FOXO1 promotes lymphomagenesis in germinal center B cells

Project description:FOXO1 acts as a tumor suppressor in solid tumors. The oncogenic PI3K pathway suppresses FOXO1 transcriptional activity by enforcing its nuclear exclusion upon AKT-mediated phosphorylation. We show here abundant nuclear expression of FOXO1 in Burkitt lymphoma (BL), a germinal center (GC) B cell derived lymphoma whose pathogenesis is linked to PI3K activation. Recurrent FOXO1 mutations which prevent AKT targeting and lock the transcription factor in the nucleus are used by BL to circumvent mutual exclusivity between PI3K and FOXO1 activation. Using genome editing in human and mouse lymphomas in which MYC and PI3K cooperate synergistically in tumor development we demonstrate pro-proliferative and anti-apoptotic activity of FOXO1 in BL and identify its nuclear localization as an oncogenic event in GC B cell derived lymphomagenesis.

2018-12-21 | GSE119437 | GEO

miR-28 expression in the Burkitt lymphoma cell line P3HR1

2014-06-01 | GSE56268 | GEO

miR-28 expression in the Burkitt lymphoma cell line P3HR1

Project description:Burkitt lymphoma (BL) is a highly aggressive B cell non-Hodgkin lymphoma (B-NHL), which originates from germinal center (GC) B cells and harbors translocations deregulating the MYC oncogene. A comparative analysis of microRNAs (miRNAs) expressed in normal and malignant GC B cells identified miR-28 as significantly down-regulated in BL, as well as in other GC-derived B-NHL. We show that re-expression of miR-28 impairs cell growth and clonogenic properties of BL cells by modulating several targets including MAD2L1, a component of the spindle checkpoint whose down-regulation is essential in mediating miR-28-induced growth-arrest, and BAG1, an activator of the ERK pathway. P3HR1 Burkitt lymphoma cell line was engineered to display inducible expression of GFP alone or GFP in combination with the miR-28 precursor from the pRTS1 vector upon doxycycline treatment. Two bulk populations (A and B) were established for both the control (GFP alone) and the miR28-expressing (GFP and miR-28 precursor) cells. Cells were induced with 0.1ug/ml doxycycline for 12h or 24h. Induction was performed on each bulk population in triplicates.

2014-06-01 | E-GEOD-56268 | biostudies-arrayexpress

c-myc-3'RR/p53+/- mice lymphomas

2012-01-05 | GSE31814 | GEO

c-myc-3'RR/p53+/- mice lymphomas

Project description:c-myc-3'RR mice prone to develop Burkitt lymphoma (BL) were crossed with p53+/- mice in order to obtain c-myc-3'RR/p53+/- mice. These mice develop a wider spectrum of lymphoma including BL, mantle cell lymphoma (MCL) and plasma cell lymphoma (PCL). Transcriptoma analysis of these lymphomas is investigated in these arrays. Four different plasma cell lymphoma (PCL1-4), three different mantle cell lymphoma (MCL1-4) and four different Burkitt lymphoma (BL1-4) were compared.

2012-01-05 | E-GEOD-31814 | biostudies-arrayexpress

Comprehensive immunophenotypic characterization of Burkitt-like lymphoma with 11q aberration by flow-cytometry

Project description:Recently, a subset of MYC-translocation negative aggressive B-cell lymphomas resembling Burkitt lymphoma (BL) characterized by proximal gains and distal losses in the long arm of chromosome 11 has been described. In the 2016 revision of the WHO classification these MYC-translocation negative lymphomas have been introduced as new provisional entity designated “Burkitt-like lymphoma with 11q aberration” (MNBLL 11q). Here, we show a comprehensive flow-cytometry analysis of 10 MNBLL 11q cases, well characterized genetically and pathologically. Twenty-three cases of MYC-positive BL, including three cases carrying both MYC rearrangements and 11q aberration, served as controls. All MNBLL 11q were CD20+/CD10+/BCL6+/BCL2- /MUM1- /MYC+/EBV negative , presented a high proliferation rate and showed a three-year overall survival (80%) similar to BL patients, with no recurrence after the end of treatment. MNBLL 11q immunophenotype was similar to that of MYC-positive BL without and with 11q, except for less frequent CD38higher expression (10% MNBLL 11q vs 91% MYC-positive BL, p<0.001), less frequent diminished CD45 expression (90% vs 23%, p=0.001), and CD16/CD56 co-expression (60% vs 0%, p<0.001). Our findings suggest subtle but important differences in MNBLL 11q immunophenotypes and MYC-positive BLs, which could not only aid in the differential diagnosis but also in the understanding of the pathogenesis of MNBLL 11q.

2019-07-30 | GSE93002 | GEO

Gene expression analysis to identify target genes of miR-150 in Hodgkin lymphoma cell lines

Project description:In Burkitt lymphoma (BL), a network consisting of MYC, MYC-repressed miR-150, known miR-150 target MYB and two novel targets of miR-150, ZDHHC11 and ZDHHC11B, has been established. This network plays an important role on the growth of BL cells. Here, we confirmed that MYB, ZDHHC11 and ZDHHC11B are targeted by miR-150 in Hodgkin lymphoma (HL) cell lines too.

2021-11-06 | GSE188310 | GEO

The EBV microRNA targetome

Project description:In EBV-associated tumors, such as gastric cancer (GC) and Burkitt’s lymphoma (BL), a high proportion of microRNAs are virally encoded. To explore the targets of both viral and host microRNAs, we performed Crosslinking, Ligation, and Sequencing of Hybrids (CLASH). With this approach, we were able to quantify each Argonaute-bound microRNA-mRNA interaction in a GC (SNU719), and BL (Akata) cell line.

2020-08-01 | GSE147228 | GEO

Elucidation of tonic and activated B cell receptor signaling in Burkitt’s lymphoma provides insights into regulation of cell survival

Project description:B-cell receptor (BCR) signaling promotes the survival of malignant B cells, such as Burkitt’s lymphoma (BL) and the activated B-cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL). In contrast to ABC DLBCL, where malignant cells require chronic activation of the BCR for their survival, BL cells are dependent on tonic BCR signaling that is antigen-independent. Elucidation and systematic comparison of tonic and activated BCR signaling led to the identification of novel signaling effectors, among them ACTN4 and ARFGEF2, which were identified as regulators of BL cell survival. As tonic and activated BCR signaling are relevant for important aspects of B cell biology, our study helps in gaining an understanding of BCR-induced processes not only in malignant but potentially also physiological settings.

2016-05-09 | PXD003492 | Pride

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