DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we ...show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.
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•Loss-of-function mutations of DDX3X are frequent in MYC-driven B cell lymphomas•DDX3X promotes translation of mRNAs encoding the core protein synthesis machinery•Loss of DDX3X buffers MYC-driven global protein synthesis and proteotoxic stress•DDX3X loss is later rescued by ectopic expression of Y-chromosome-encoded DDX3Y
Gong et al. show that during the early stages of lymphoma development, loss-of-function mutations in the RNA helicase DDX3X allow human B cells to tolerate the forced expression of MYC. In contrast, established tumors restore DDX3 helicase activity by ectopic expression of the Y-chromosome-encoded homolog DDX3Y.
Hepatocellular carcinoma (HCC) commonly develops in patients with underlying chronic liver disease. Additionally, the tumorous lesions of HCC patients are consistently characterized by the lack of ...iron accumulation even when arising in iron-loaded liver. However, the molecular mechanism leading to this observed phenomenon is currently poorly understood. In this study, all tumorous tissues from 24 HCC patients with chronic HBV infection were stained negative for iron when histologically assessed by Perls' Prussian blue stain, whereas excess iron deposits were present in 17 of the 24 adjacent non-tumorous liver tissues. To elucidate the concerted regulation of iron homeostasis in these patients, we studied the gene expression profiling of 42 relevant iron-regulatory genes in the tumorous and adjacent non-tumorous liver tissues of these HCC patients along with 10 normal liver controls. Expression for most of the iron-regulatory genes, including hepcidin, transferrin receptor 2 (TfR2), transferrin (Tf), ceruloplasmin (Cp) and iron regulatory protein 1 (IRP1), were significantly down-regulated in the tumorous tissues of these patients compared to the adjacent non-tumorous liver tissues and normal liver controls. On the other hand, expression of hepcidin, TfR2, ferroportin 1 and DMT1 were significantly up-regulated in iron-loaded non-cirrhotic non-tumorous liver tissues as compared with normal liver controls. Hence, the reduction of hepcidin expression within the iron-depleted tumorous lesions likely reflects the physiological consequence of the obligate demand for iron in the rapidly growing neoplastic cells, whereas the up-regulation of hepcidin expression in the iron-loaded adjacent non-tumorous liver tissues is likely a physiological response.
Abstract
Background
Accumulating data demonstrate that Fyn tyrosine kinase is involved in oligomeric amyloid‐β toxicity and tau pathology in Alzheimer's disease (AD). We reported that selective ...up‐regulation of FynT isoform in post‐mortem AD brains was associated with tau pathology and neuroinflammation (Lee
et al
., 2016). Furthermore, our preliminary data demonstrated that FynT induction could be recapitulated in aged P301S mutant human tau transgenic mice, which also correlated significantly with tau pathology and neuroinflammation. We thus hypothesize that FynT could be the pathogenic isoform of Fyn in AD. In this study, we generate double transgenic model by knocking out FynT in P301S mice and monitor the possible protective effects on disease progression.
Method
FynT‐knockout (KO) is a transgenic model with specific knockdown of FynT isoform but retains FynB expression. Double transgenic mice (DTg) have been generated by crossing KO with P301S mutant human tau transgenic mice. HTRF technology‐based Cisbio assay kits, real‐time RT‐PCR and immunoblots are used to monitor changes of tau pathology, neuroinflammation and synaptic markers in the brains, respectively.
Result
Subsequent studies were conducted and analyzed in males because we noticed that P301S males significantly manifested more severe tau pathology and neuroinflammation than P301S females. Significant decrease of phosphorylated tau, aggregated tau and GFAP expression were detected in DTg when compared with P301S. Consistently, reduction of synaptic markers in P301S mice can also be rescued by depletion of FynT in DTg.
Conclusion
Selective knocking out of FynT isoform led to the attenuation of tau pathology, neuroinflammation and synaptic degeneration in mice with P301S background. This suggests that FynT could be the pathogenic isoform of Fyn in AD. This study further ascertains the isoform‐specific role of FynT as a therapeutic target for AD.
Abstract
Background
Fyn tyrosine kinase is involved in the disease progression of Alzheimer’s disease (AD). Our lab has previously reported an isoform‐specific role of FynT tyrosine kinase in AD ...brain which is associated with neurodegeneration and reactive astrogliosis Lee et al., 2016. In view of AD‐related neuropathology and neuroinflammation were not exclusively found in AD, the objective of the study is to investigate whether differential alternative splicing of Fyn to favour FynT expression could also be detected in other neurodegenerative dementias including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).
Method
Post‐mortem human brain tissues (prefrontal cortex Brodmann area 9 (BA9) and temporal cortex (BA21) derived from subjects diagnosed with AD, DLB, PDD, as well as controls (CTRL) without neurological or psychiatric diseases were provided by the Brains for Dementia Research (BDR). The brain tissues were recorded for Mini‐Mental State Examination (MMSE) and Braak staging. The brain tissues were processed accordingly for ELISA, real‐time PCR, capillary electrophoresis and HTA array studies.
Result
Selective and significant up‐regulation of FynT isoform expression in prefrontal and temporal cortex of AD, DLB and PDD when compared with CTRL was observed to significantly correlate with cognitive impairment and neuropathological characteristics. FynT induction in AD, DLB and PDD was associated with neuroinflammatory markers. Synaptic dysfunction could be the adverse impacts of FynT induction in neurodegenerative dementias.
Conclusion
Using an independent cohort, we reported that FynT induction was not exclusive to AD, but also detected in neurodegenerative dementia including DLB and PDD. FynT induction was closely associated with tau pathology and neuroinflammation, which likely contributed to synaptic dysfunction and cognitive impairment. Potential therapeutic treatment should specifically target the disease‐associated isoform of Fyn.
Background
Fyn tyrosine kinase is involved in the disease progression of Alzheimer’s disease (AD). Our lab has previously reported an isoform‐specific role of FynT tyrosine kinase in AD brain which ...is associated with neurodegeneration and reactive astrogliosis Lee et al., 2016. In view of AD‐related neuropathology and neuroinflammation were not exclusively found in AD, the objective of the study is to investigate whether differential alternative splicing of Fyn to favour FynT expression could also be detected in other neurodegenerative dementias including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD).
Method
Post‐mortem human brain tissues (prefrontal cortex Brodmann area 9 (BA9) and temporal cortex (BA21) derived from subjects diagnosed with AD, DLB, PDD, as well as controls (CTRL) without neurological or psychiatric diseases were provided by the Brains for Dementia Research (BDR). The brain tissues were recorded for Mini‐Mental State Examination (MMSE) and Braak staging. The brain tissues were processed accordingly for ELISA, real‐time PCR, capillary electrophoresis and HTA array studies.
Result
Selective and significant up‐regulation of FynT isoform expression in prefrontal and temporal cortex of AD, DLB and PDD when compared with CTRL was observed to significantly correlate with cognitive impairment and neuropathological characteristics. FynT induction in AD, DLB and PDD was associated with neuroinflammatory markers. Synaptic dysfunction could be the adverse impacts of FynT induction in neurodegenerative dementias.
Conclusion
Using an independent cohort, we reported that FynT induction was not exclusive to AD, but also detected in neurodegenerative dementia including DLB and PDD. FynT induction was closely associated with tau pathology and neuroinflammation, which likely contributed to synaptic dysfunction and cognitive impairment. Potential therapeutic treatment should specifically target the disease‐associated isoform of Fyn.
Background
Accumulating data demonstrate that Fyn tyrosine kinase is involved in oligomeric amyloid‐β toxicity and tau pathology in Alzheimer's disease (AD). We reported that selective up‐regulation ...of FynT isoform in post‐mortem AD brains was associated with tau pathology and neuroinflammation (Lee et al., 2016). Furthermore, our preliminary data demonstrated that FynT induction could be recapitulated in aged P301S mutant human tau transgenic mice, which also correlated significantly with tau pathology and neuroinflammation. We thus hypothesize that FynT could be the pathogenic isoform of Fyn in AD. In this study, we generate double transgenic model by knocking out FynT in P301S mice and monitor the possible protective effects on disease progression.
Method
FynT‐knockout (KO) is a transgenic model with specific knockdown of FynT isoform but retains FynB expression. Double transgenic mice (DTg) have been generated by crossing KO with P301S mutant human tau transgenic mice. HTRF technology‐based Cisbio assay kits, real‐time RT‐PCR and immunoblots are used to monitor changes of tau pathology, neuroinflammation and synaptic markers in the brains, respectively.
Result
Subsequent studies were conducted and analyzed in males because we noticed that P301S males significantly manifested more severe tau pathology and neuroinflammation than P301S females. Significant decrease of phosphorylated tau, aggregated tau and GFAP expression were detected in DTg when compared with P301S. Consistently, reduction of synaptic markers in P301S mice can also be rescued by depletion of FynT in DTg.
Conclusion
Selective knocking out of FynT isoform led to the attenuation of tau pathology, neuroinflammation and synaptic degeneration in mice with P301S background. This suggests that FynT could be the pathogenic isoform of Fyn in AD. This study further ascertains the isoform‐specific role of FynT as a therapeutic target for AD.
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