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Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis.

ABSTRACT: In Burkitt lymphoma (BL), a germinal center B-cell-derived tumor, the pro-apoptotic properties of c-MYC must be counterbalanced. Predicting that survival signals would be delivered by phosphoinositide-3-kinase (PI3K), a major survival determinant in mature B cells, we indeed found that combining constitutive c-MYC expression and PI3K activity in germinal center B cells of the mouse led to BL-like tumors, which fully phenocopy human BL with regard to histology, surface and other markers, and gene expression profile. The tumors also accumulate tertiary mutational events, some of which are recurrent in the human disease. These results and our finding of recurrent PI3K pathway activation in human BL indicate that deregulated c-MYC and PI3K activity cooperate in BL pathogenesis.

SUBMITTER: Sander S

PROVIDER: S-EPMC3432451 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis.

Sander Sandrine S Calado Dinis P DP Srinivasan Lakshmi L Köchert Karl K Zhang Baochun B Rosolowski Maciej M Rodig Scott J SJ Holzmann Karlheinz K Stilgenbauer Stephan S Siebert Reiner R Bullinger Lars L Rajewsky Klaus K

Cancer cell 20120801 2

In Burkitt lymphoma (BL), a germinal center B-cell-derived tumor, the pro-apoptotic properties of c-MYC must be counterbalanced. Predicting that survival signals would be delivered by phosphoinositide-3-kinase (PI3K), a major survival determinant in mature B cells, we indeed found that combining constitutive c-MYC expression and PI3K activity in germinal center B cells of the mouse led to BL-like tumors, which fully phenocopy human BL with regard to histology, surface and other markers, and gene ...[more]

PMID: 22897848

Similar Datasets

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

Synergy between PI3K Signaling and MYC in Burkitt Lymphomagenesis

2012-08-14 | GSE35219 | GEO

Wnt signaling mediates oncogenic synergy between Akt and Dlx5 in T-cell lymphomagenesis by enhancing cholesterol synthesis.

Project description:The Dlx5 homeobox gene was first implicated as an oncogene in a T-ALL mouse model expressing myristoylated (Myr) Akt2. Furthermore, overexpression of Dlx5 was sufficient to drive T-ALL in mice by directly activating Akt and Notch signaling. These findings implied that Akt2 cooperates with Dlx5 in T-cell lymphomagenesis. To test this hypothesis, Lck-Dlx5;Lck-MyrAkt2 transgenic mice were generated. MyrAkt2 synergized with Dlx5 to greatly accelerate and enhance the dissemination of T-lymphomagenesis. RNA-seq analysis performed on lymphomas from Lck-Dlx5;Lck-MyrAkt mice revealed upregulation of genes involved in the Wnt and cholesterol biosynthesis pathways. Combined RNA-seq and ChIP-seq analysis of lymphomas from Lck-Dlx5;Lck-MyrAkt mice demonstrated that β-catenin directly regulates genes involved in sterol regulatory element binding transcription factor 2 (Srebf2)-cholesterol synthesis. These lymphoma cells had high Lef1 levels and were highly sensitive to β-catenin and Srebf2-cholesterol synthesis inhibitors. Similarly, human T-ALL cell lines with activated NOTCH and AKT and elevated LEF1 levels were sensitive to inhibition of β-catenin and cholesterol pathways. Furthermore, LEF1 expression positively correlated with expression of genes involved in the cholesterol synthesis pathway in primary human T-ALL specimens. Together, these data suggest that targeting β-catenin and/or cholesterol biosynthesis, together with AKT, could have therapeutic efficacy in a subset of T-ALL patients.

| S-EPMC7522078 | biostudies-literature

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis.

Project description:Although the Myc transcription factor has been shown necessary for the oncogenic function of Ras, the contribution of Ras pathway signaling to the oncogenic function of Myc remains unresolved. We report the novel findings that Myc alone induced Ras/Mapk pathway signaling, and increased signaling following growth factor stimulation. Deletion of the scaffold protein kinase suppressor of Ras 1 (Ksr1) attenuated signaling through the Ras/Mapk pathway, including activation following Myc induction. B cells that lacked Ksr1 exhibited reduced proliferation and increased cytokine deprivation-induced apoptosis. Overexpression of Myc rescued the proliferation defect of Ksr1-null B cells, but loss of Ksr1 increased sensitivity of B cells to Myc-induced apoptosis. Notably, there was a significant delay in lymphoma development in Ksr1-null mice overexpressing Myc in B cells (Eμ-myc transgenic mice). There was an elevated frequency of p53 inactivation, indicative of increased selective pressure to bypass the p53 tumor suppressor pathway, in Ksr1-null Eμ-myc lymphomas. Therefore, loss of Ksr1 inhibits Ras/Mapk pathway signaling leading to increased Myc-induced B-cell apoptosis, and this results in reduced B-cell transformation and lymphoma development. Our data indicate that suppression of Myc-induced Ras/Mapk pathway signaling significantly impairs Myc oncogenic function. These results fill a significant gap in knowledge about Myc and should open new avenues of therapeutic intervention for Myc-overexpressing malignancies.

| S-EPMC3374085 | biostudies-other

FoxO3 suppresses Myc-driven lymphomagenesis.

Project description:This study demonstrates, for the first time, that loss of a single forkhead box class O (FoxO) transcription factor, can promote lymphomagenesis. Using two different mouse models, we show that FoxO3 has a significant tumour-suppressor function in the context of Myc-driven lymphomagenesis. Loss of FoxO3 significantly accelerated myeloid tumorigenesis in vavP-MYC10 transgenic mice and B lymphomagenesis in E?-myc transgenic mice. Tumour analysis indicated that the selective pressure for mutation of the p53 pathway during E?-myc lymphomagenesis was not altered. Frank tumours were preceded by elevated macrophage numbers in FoxO3(-/-) vavP-MYC10 mice but, surprisingly, pre-B-cell numbers were relatively normal in healthy young FoxO3(-/-)E?-myc mice. In vitro assays revealed enhanced survival capacity of Myc-driven cells lacking FoxO3, but no change in cell cycling was detected. The loss of FoxO3 may also be affecting other tumour-suppressive functions for which FoxO1/4 cannot fully compensate.

| S-EPMC4816178 | biostudies-literature

Mnt modulates Myc-driven lymphomagenesis.

Project description:The transcriptional represser Mnt is a functional antagonist of the proto-oncoprotein Myc. Both Mnt and Myc utilise Max as an obligate partner for DNA binding, and Myc/Max and Mnt/Max complexes compete for occupancy at E-box DNA sequences in promoter regions. We have previously shown in transgenic mouse models that the phenotype and kinetics of onset of haemopoietic tumours varies with the level of Myc expression. We reasoned that a decrease in the level of Mnt would increase the functional level of Myc and accelerate Myc-driven tumorigenesis. We tested the impact of reduced Mnt in three models of myc transgenic mice and in p53+/- mice. To our surprise, mnt heterozygosity actually slowed Myc-driven tumorigenesis in vavP-MYC10 and E?-myc mice, suggesting that Mnt facilitates Myc-driven oncogenesis. To explore the underlying cause of the delay in tumour development, we enumerated Myc-driven cell populations in healthy young vavP-MYC10 and E?-myc mice, expecting that the reduced rate of leukaemogenesis in mnt heterozygous mice would be reflected in a reduced number of preleukaemic cells, due to increased apoptosis or reduced proliferation or both. However, no differences were apparent. Furthermore, when mnt+/+ and mnt+/- pre-B cells from healthy young E?-myc mice were compared in vitro, no differences were seen in their sensitivity to apoptosis or in cell size or cell cycling. Moreover, the frequencies of apoptotic, senescent and proliferating cells were comparable in vivo in mnt+/- and mnt+/+ E?-myc lymphomas. Thus, although mnt heterozygosity clearly slowed lymphomagenesis in vavP-MYC10 and E?-myc mice, the change(s) in cellular properties responsible for this effect remain to be identified.

| S-EPMC5686348 | biostudies-literature

Myc suppression of Nfkb2 accelerates lymphomagenesis.

Project description:BackgroundDeregulated c-Myc expression is a hallmark of several human cancers where it promotes proliferation and an aggressive tumour phenotype. Myc overexpression is associated with reduced activity of Rel/NF-kappaB, transcription factors that control the immune response, cell survival, and transformation, and that are frequently altered in cancer. The Rel/NF-kappaB family member NFKB2 is altered by chromosomal translocations or deletions in lymphoid malignancies and deletion of the C-terminal ankyrin domain of NF-kappaB2 augments lymphocyte proliferation.MethodsPrecancerous Emicro-Myc-transgenic B cells, Emicro-Myc lymphomas and human Burkitt lymphoma samples were assessed for Nfkb2 expression. The contribution of Nfkb2 to Myc-driven apoptosis, proliferation, and lymphomagenesis was tested genetically in vivo.ResultsHere we report that the Myc oncoprotein suppresses Nfkb2 expression in vitro in primary mouse fibroblasts and B cells, and in vivo in the Emicro-Myc transgenic mouse model of human Burkitt lymphoma (BL). NFKB2 suppression by Myc was also confirmed in primary human BL. Promoter-reporter assays indicate that Myc-mediated suppression of Nfkb2 occurs at the level of transcription. The contribution of Nfkb2 to Myc-driven lymphomagenesis was tested in vivo, where Nfkb2 loss was shown to accelerate lymphoma development in Emicro-Myc transgenic mice, by impairing Myc's apoptotic response.ConclusionsNfkb2 is suppressed by c-Myc and harnesses Myc-driven lymphomagenesis. These data thus link Myc-driven lymphomagenesis to the non-canonical NF-kappaB pathway.

| S-EPMC2902445 | biostudies-literature

PIAS1 Promotes Lymphomagenesis through MYC Upregulation.

Project description:The MYC proto-oncogene is a transcription factor implicated in a broad range of cancers. MYC is regulated by several post-translational modifications including SUMOylation, but the functional impact of this post-translational modification is still unclear. Here, we report that the SUMO E3 ligase PIAS1 SUMOylates MYC. We demonstrate that PIAS1 promotes, in a SUMOylation-dependent manner, MYC phosphorylation at serine 62 and dephosphorylation at threonine 58. These events reduce the MYC turnover, leading to increased transcriptional activity. Furthermore, we find that MYC is SUMOylated in primary B cell lymphomas and that PIAS1 is required for the viability of MYC-dependent B cell lymphoma cells as well as several cancer cell lines of epithelial origin. Finally, Pias1-null mice display endothelial defects reminiscent of Myc-null mice. Taken together, these results indicate that PIAS1 is a positive regulator of MYC.

| S-EPMC4899214 | biostudies-literature

Wnt Signaling Mediates Oncogenic Synergy Between Akt and Dlx5 in T-Cell Lymphomagenesis by Enhancing Cholesterol Synthesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-07 | GSE149350 | GEO

Role of MYC in B Cell Lymphomagenesis.

Project description:B cell lymphomas mainly arise from different developmental stages of B cells in germinal centers of secondary lymphoid tissue. There are a number of signaling pathways that affect the initiation and development of B cell lymphomagenesis. The functions of several key proteins that represent branching points of signaling networks are changed because of their aberrant expression, degradation, and/or accumulation, and those events determine the fate of the affected B cells. One of the most influential transcription factors, commonly associated with unfavorable prognosis for patients with B cell lymphoma, is nuclear phosphoprotein MYC. During B cell lymphomagenesis, oncogenic MYC variant is deregulated through various mechanisms, such as gene translocation, gene amplification, and epigenetic deregulation of its expression. Owing to alterations of downstream signaling cascades, MYC-overexpressing neoplastic B cells proliferate rapidly, avoid apoptosis, and become unresponsive to most conventional treatments. This review will summarize the roles of MYC in B cell development and oncogenesis, as well as its significance for current B cell lymphoma classification. We compared communication networks within transformed B cells in different lymphomas affected by overexpressed MYC and conducted a meta-analysis concerning the association of MYC with tumor prognosis in different patient populations.

| S-EPMC5406862 | biostudies-literature

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