STAT6 mutations compensate for CREBBP mutations and hyperactivate IL4/STAT6/RRAGD/mTOR signaling in Follicular Lymphoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1177783 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR31113913_1.fastq.gz | Fastqsanger.gz | |||
| SRR31113913_2.fastq.gz | Fastqsanger.gz | |||
| SRR31113914_1.fastq.gz | Fastqsanger.gz | |||
| SRR31113914_2.fastq.gz | Fastqsanger.gz |
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Project description:Activating mutations in STAT6 are common in Follicular Lymphoma (FL) and transformed FL and various other B cell lymphomas. Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC; N = 6), and primary human FL WT (N = 11) or mutant (N = 4) for STAT6 before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT STAT6 we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with STAT6 mutations. We tracked the attenuated IL4/JAK/STAT6 response to co-existing CREBBP mutations and experimentally verified that intact CREBBP is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is RRAGD, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by CREBBP mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.
2025-03-10 | GSE261465 | GEO
Project description:Activating mutations in STAT6 are common in Follicular Lymphoma (FL) and transformed FL and various other B cell lymphomas. Here, we report RNA-seq based gene expression data on normal human lymph node derived B lymphocytes (NBC; N = 6), and primary human FL WT (N = 11) or mutant (N = 4) for STAT6 before and after ex vivo stimulation with IL4. We found that STAT6 mutants result in broad based augmentation of IL4-induced gene expression. Unexpectedly, in FL with WT STAT6 we measured reduced baseline and IL4-induced gene expression levels when compared with NBC lymphocytes or FL with STAT6 mutations. We tracked the attenuated IL4/JAK/STAT6 response to co-existing CREBBP mutations and experimentally verified that intact CREBBP is required for the induction of many IL4-induced genes. One of the IL4-induced genes here identified is RRAGD, a small G-protein involved in lysosomal mTOR activation. We show that IL4 treatment induced RRAGD expression, that RRAGD is required for mTOR activation in lymphoma cells and that IL4-enhanced BCR signaling induced mTOR activation. The IL4 and BCR-induced mTOR activation was reduced by CREBBP mutants and augmented by mutant STAT6, establishing a link between STAT6 mutations and mTOR regulated pro-growth pathways in lymphoma.
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Project description:STAT6 mutations compensate for CREBBP mutations and hyperactivate IL4/STAT6/RRAGD/mTOR signaling in follicular lymphoma
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Project description:Inactivating mutations of the CREBBP acetyltransferase and, at lower frequencies, its paralogue EP300 are among the most common genetic alterations in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most frequent B cell malignancies. Here we uncover unexpected distinct functions for CREBBP and EP300 in the germinal center (GC), i.e. the target structure for most human B cell lymphomas. We show that these proteins modulate non-overlapping transcriptional programs that are preferentially enriched in biological functions associated with the separate anatomic compartments of the GC. Consistently, deletion of CREBBP or EP300 have opposing effects on GC formation in vivo. Nonetheless, these proteins partially compensate for each other to maintain a minimal threshold of acetyltransferase activity and guarantee homeostatic control of the GC, which is completely abrogated by their combined loss. This synthetic lethal interaction is retained in DLBCL cells, identifying an Achille’s heel in CREBBP-mutant lymphomas that could be pharmacologically targeted by using a novel, selective small molecule inhibitor of the CREBBP/EP300 bromodomain. These data shed light on the unique roles of CREBBP and EP300 in the physiology and pathology of GC B cells, and provide a proof-of-principle for the development and testing of EP300 inhibition as a therapeutic strategy in these diseases.
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Project description:We demonstrate that STAT3 and STAT6 significantly activated after IL4 treatment in EML4-ALK postive lung cancer cell lines The aim of this study was to explore whether IL4 could activate the JAK2-STAT pathway in EML4-ALK-positive cells.
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Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.
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Project description:Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic Hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide novel insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. We used microarrays to detail the global programme of gene expression underlying the knockout of Crebbp in murine Shh medulloblastoma, acutely induced at postnatal stages of development.
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Project description:Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic Hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide novel insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases. We used microarrays to detail the global programme of gene expression underlying the knockout of Crebbp in murine granule neuron precursors, chronically induced at embryonic stages of development.
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