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The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE190671 | GEO | 2022/12/31

REPOSITORIES: GEO

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The polyamine-hypusine circuit controls an oncogenic translational program necessary for MYC-driven lymphomagenesis

Project description:MYC oncogenes are activated in broad spectrum of human malignancies and transcriptionally reprogram the genome to drive cancer cell growth. Given this it is unclear if targeting a single effector will have a therapeutic benefit. MYC activates the polyaminehypusine circuit, which post-translationally modifies the translation factor eIF5A. The hypusine axis has been proposed to suppress tumorigenesis. Here we report essential roles for hypusinated eIF5A in the development and maintenance of Myc-driven lymphoma, where loss of eIF5A hypusination abolishes malignant transformation. Mechanistically, integrating RNA-seq, Ribo-seq and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including key regulators of G1 to S phase cell cycle progression. Notably, this circuit controls Myc’s proliferative response at several levels, and it is activated across multiple tumor types. These findings suggest the hypusine circuit as a therapeutic target for a broad spectrum of malignancies.

2024-01-26 | PXD031361 | Pride

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [Ribo-seq]

Project description:Hypusinated EiF5A likely impacts diverse cellular pathways through direct regulation of its translational targets or via secondary effects on other biological processes. We examined the global effects of knockdown of EiF5A and Dhps on the transcriptome and translational landscape of MYC-induced lymphoma.

2022-12-31 | GSE190670 | GEO

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [RNA-seq]

Project description:Hypusinated EiF5A likely impacts diverse cellular pathways, through direct regulation of its translational targets or via secondary effects on other biological processes. We examined the global effects of knockdown of EiF5A and Dhps on the transcriptome and translational landscape of MYC-induced lymphoma.

2022-12-31 | GSE190669 | GEO

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Essential for Malignant Conversion in MYC-Driven Lymphoma.

Project description:The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given this, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine-hypusine circuit, which posttranslationally modifies the eukaryotic translation factor eIF5A. The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where the loss of eIF5A hypusination abolishes malignant transformation of MYC-overexpressing B cells. Mechanistically, integrating RNA sequencing, ribosome sequencing, and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1-S phase cell-cycle progression and DNA replication. This circuit thus controls MYC's proliferative response, and it is also activated across multiple malignancies. These findings suggest the hypusine circuit as a therapeutic target for several human tumor types.SignificanceElevated EIF5A and the polyamine-hypusine circuit are manifest in many malignancies, including MYC-driven tumors, and eIF5A hypusination is necessary for MYC proliferative signaling. Not-ably, this circuit controls an oncogenic translational program essential for the development and maintenance of MYC-driven lymphoma, supporting this axis as a target for cancer prevention and treatment. See related commentary by Wilson and Klein, p. 248. This article is highlighted in the In This Issue feature, p. 247.

| S-EPMC10320645 | biostudies-literature

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis

Project description:The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis

| PRJNA787942 | ENA

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [Ribo-seq]

Project description:The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [Ribo-seq]

| PRJNA787943 | ENA

The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [RNA-seq]

Project description:The Polyamine-Hypusine Circuit Controls an Oncogenic Translational Program Necessary for MYC-Driven Lymphomagenesis [RNA-seq]

| PRJNA787944 | ENA

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 Eμ-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 Eμ-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 Eμ-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+/+ Eμ-myc lymphomas. Thus, although mnt heterozygosity clearly slowed lymphomagenesis in vavP-MYC10 and Eμ-myc mice, the change(s) in cellular properties responsible for this effect remain to be identified.

| S-EPMC5686348 | biostudies-literature

Myc controls NK cell development, IL-15-driven expansion, and translational machinery.

Project description:MYC is a pleiotropic transcription factor involved in cancer, cell proliferation, and metabolism. Its regulation and function in NK cells, which are innate cytotoxic lymphocytes important to control viral infections and cancer, remain poorly defined. Here, we show that mice deficient for Myc in NK cells presented a severe reduction in these lymphocytes. Myc was required for NK cell development and expansion in response to the key cytokine IL-15, which induced Myc through transcriptional and posttranslational mechanisms. Mechanistically, Myc ablation in vivo largely impacted NK cells' ribosomagenesis, reducing their translation and expansion capacities. Similar results were obtained by inhibiting MYC in human NK cells. Impairing translation by pharmacological intervention phenocopied the consequences of deleting or blocking MYC in vitro. Notably, mice lacking Myc in NK cells exhibited defective anticancer immunity, which reflected their decreased numbers of mature NK cells exerting suboptimal cytotoxic functions. These results indicate that MYC is a central node in NK cells, connecting IL-15 to translational fitness, expansion, and anticancer immunity.

| S-EPMC10140547 | biostudies-literature

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