Targeting the PI3K/AKT/mTOR Signaling Pathway in Primary Central Nervous System Lymphoma: Current Status and Future Prospects

Primary Central Nervous System Lymphoma (PCNSL) is a rare invasive extranodal non- Hodgkin lymphoma, a vast majority of which is Diffuse Large B-Cell Lymphoma (DLBCL). Although high-dose methotrexate-based immunochemotherapy achieves a high remission rate, the risk of relapse and related death remains a crucial obstruction to long-term survival. Novel agents for the treatment of lymphatic malignancies have significantly broadened the horizons of therapeutic options for PCNSL. The PI3K/AKT/mTOR signaling pathway is one of the most important pathways for Bcell malignancy growth and survival. Novel therapies that target key components of this pathway have shown antitumor effects in many B-cell malignancies, including DLBCL. This review will discuss the aberrant status of the PI3K/AKT/mTOR signaling pathways in PCNSL and the application prospects of inhibitors in hopes of providing alternative clinical therapeutic strategies and improving prognosis.

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The PI3K/AKT/mTOR signaling pathway is aberrantly activated in primary central nervous system lymphoma and correlated with a poor prognosis.

10.21203/rs.3.rs-793020/v1 ◽

2021 ◽

Author(s):

Yuanbo Liu

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Correlation Analysis ◽

Mrna Expression ◽

Signaling Pathway ◽

Poor Prognosis ◽

Central Nervous System Lymphoma ◽

Mtor Signaling ◽

Control Group ◽

Mtor Signaling Pathway

Abstract Background Primary central nervous system lymphoma (PCNSL) is a specific subtype of non-Hodgkin lymphoma that is highly invasive and confined to the central nervous system (CNS). The vast majority of PCNSLs are diffuse large B-cell lymphomas (DLBCLs). PCNSL is a highly heterogeneous disease, and its pathogenesis has not yet been fully elucidated. Further studies are needed to guide individualized therapy and improve the prognosis. Methods In this study, we detected 1) the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 by immunohistochemistry (IHC) and Western blotting, 2) the mRNA expression by real-time qPCR and 3) the deletion of PTEN gene by immunofluorescence in situ hybridization (FISH) in order to investigate the activation status of the PI3K/AKT/mTOR signaling pathway in PCNSL. Samples of reactive hyperplasia lymphnods were used as the control group. The correlations between the clinical characteristics and prognosis of PCNSL patients and the expression of p-AKT, p-mTOR, p-S6 and p-4E-BP1 and the deletion of PTEN were assessed. Results The IHC results showed that the positive expression rates of p-AKT, p-mTOR, p-S6 and p-4E-BP1 in PCNSL were significantly higher in the PCNSL group than in the control group (P < 0.05). The relative mRNA expression level of MTOR in PCNSL samples was significantly increased (P = 0.013). Correlation analysis revealed that the expression of p-mTOR was correlated with that of p-AKT, p-S6, p-4E-BP1. PTEN deletion was found in 18.9% of PCNSL samples and was correlated with the expression of p-AKT (P = 0.031). Correlation analysis revealed that the PCNSL relapse rate in the p-mTOR-positive group was 64.5%, significantly higher than that in the negative group (P = 0.001). Kaplan-Meier survival analysis showed inferior progression-free survival (PFS) in the p-mTOR- and p-S6-positive groups (P = 0.002 and 0.009, respectively), and PTEN deletion tended to be related to shorter overall survival (OS) (P = 0.072). Cox regression analysis revealed p-mTOR expression as an independent prognostic factor for a shorter PFS (hazard ratio (HR) = 7.849, P = 0.046). Conclusions Our results suggest that the PI3K/AKT/mTOR signaling pathway is aberrantly activated in PCNSL and associated with a poor prognosis, which might indicate new therapeutic targets and prognostic factors.

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Primary Central Nervous System Lymphoma Mimicking Longitudinally Extensive Transverse Myelitis

The Neurohospitalist ◽

10.1177/1941874420967560 ◽

2020 ◽

pp. 194187442096756

Author(s):

Prashant Anegondi Natteru ◽

Shashank Shekhar ◽

Lakshmi Ramachandran Nair ◽

Hartmut Uschmann

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Oligoclonal Bands ◽

Relative Reduction ◽

Thalamic Lesion ◽

The Right

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extra-nodal non-Hodgkin’s lymphoma. Three regions can be involved in PCNSL: the brain, the spine, or the vitreus and retina. Spinal PCNSL is rare. It can mimic neoplasm, infection, and inflammation. Diagnostic confirmation is by tissue biopsy, and even then, tissue corroboration may be altered by an inflammatory overlay. We report a 59-year-old woman who we saw after she had 4 weeks of ascending tetraparesis plus bowel and bladder incontinence. Upon presentation, the patient was ventilator-dependent and locked-in. She reported normal sensation through eye-blinking. Magnetic resonance imaging (MRI) brain revealed signal intensity in the bilateral corona radiata and restricted diffusion in the right thalamus, whereas, MRI cervical, and thoracic spine showed T2 prolongation in the anterior medulla and upper cervical cord, with enhancement to C2-C3, and long segment hyperintensity from T1-T9 levels, respectively, suggestive of neuromyelitis optica spectrum disorder. Cerebrospinal fluid cytomorphology and flow cytometry were inconclusive for lymphoma/leukemia, but oligoclonal bands were present. Serum aquaporin-4 (AQP-4) antibodies were negative. MR spectroscopy demonstrated NAA reduction, mild lipid lactate peak, and relative reduction of choline on the side of the lesion, favoring demyelination. She received 5-days of intravenous methylprednisolone, followed by 7 sessions of plasma exchange without clinical improvement. Stereotactic biopsy of the right thalamic lesion revealed diffuse large B-cell lymphoma. PCNSL can mimic a demyelinating process early on, as steroid treatment could disrupt B-cell lymphoma cells, thus masking the correct diagnosis.

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T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Presenting as a Primary Central Nervous System Lymphoma

Rare Tumors ◽

10.4081/rt.2015.6084 ◽

2015 ◽

Vol 7 (4) ◽

pp. 160-162 ◽

Cited By ~ 1

Author(s):

Pooja Advani ◽

Jason Starr ◽

Abhisek Swaika ◽

Liuyan Jiang ◽

Yushi Qiu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

T Cell ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Pathway analysis of primary central nervous system lymphoma

Blood ◽

10.1182/blood-2007-10-119099 ◽

2008 ◽

Vol 111 (6) ◽

pp. 3200-3210 ◽

Cited By ~ 106

Author(s):

Han W. Tun ◽

David Personett ◽

Karen A. Baskerville ◽

David M. Menke ◽

Kurt A. Jaeckle ◽

...

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Pathway Analysis ◽

Metastatic Cancer ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Significant Differential Expression ◽

A Genome

Abstract Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true “CNS signature” because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

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Single cell transcriptomic analysis of diffuse large B cells in cerebrospinal fluid of central nervous system lymphoma

10.1101/2020.04.18.20065805 ◽

2020 ◽

Author(s):

Haoyu Ruan ◽

Zhe Wang ◽

Yue Zhai ◽

Ying Xu ◽

Linyu Pi ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

B Cells ◽

B Cell ◽

Single Cell ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Great Promise ◽

Leptomeningeal Involvement

AbstractDiffuse large B-cell lymphoma (DLBCL) is the predominant type of central nervous system lymphoma (CNSL) including primary CNSL and secondary CNSL. Diffuse large B cells in cerebrospinal fluid (CSF-DLBCs) have offered great promise for the diagnostics and therapeutics of CNSL leptomeningeal involvement. To explore the distinct phenotypic states of CSF-DLBCs, we analyzed the transcriptomes of 902 CSF-DLBCs from six CNSL-DLBCL patients using single-cell RNA sequencing technology. We defined CSF-DLBCs based on abundant expression of B-cell markers, as well as the enrichment of cell proliferation and energy metabolism pathways. CSF-DLBCs within individual patients exhibited monoclonality with similar variable region of light chains (VL) expression. It is noteworthy that we observed some CSF-DLBCs have double classes of VL (lambda and kappa) transcripts. We identified substantial heterogeneity in CSF-DLBCs, and found significantly greater among-patient heterogeneity compared to among-cell heterogeneity within a given patient. The transcriptional heterogeneity across CSF-DLBCs is manifested in cell cycle state and cancer-testis antigens expression. Our results will provide insight into the mechanism research and new diagnostic direction of CNSL-DLBCL leptomeningeal involvement.

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Primary Central Nervous System Lymphoma: Diffuse Large B-Cell Lymphoma

Turkish Journal Of Neurology ◽

10.4274/tnd.2019.41882 ◽

2019 ◽

Vol 25 (4) ◽

pp. 239-242

Author(s):

Asuman Ali ◽

Cemile Haki ◽

Fatma Öz Atalay ◽

Ramazan Yalçın

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Intravascular large B-cell lymphoma as a recurrence of primary central nervous system lymphoma after chemotherapy: A case report

Leukemia Research Reports ◽

10.1016/j.lrr.2021.100249 ◽

2021 ◽

pp. 100249

Author(s):

Yoko Edahiro ◽

Tomoiku Takaku ◽

Mario Suzuki ◽

Yasutaka Fukuda ◽

Sakiko Harada ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Case Report ◽

B Cell ◽

Cell Lymphoma ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Update on Atypicalities of Central Nervous System in Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci10050309 ◽

2020 ◽

Vol 10 (5) ◽

pp. 309

Author(s):

Ahmad Naqib Shuid ◽

Putri Ayu Jayusman ◽

Nazrun Shuid ◽

Juriza Ismail ◽

Norazlin Kamal Nor ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Central Nervous System ◽

Nervous System ◽

Signaling Pathway ◽

Immune Dysregulation ◽

Autism Spectrum ◽

Mtor Signaling ◽

Spectrum Disorder ◽

Mtor Signaling Pathway ◽

And Function

Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined, neurodevelopmental disorder that has been modeled as a brain-based disease. The behavioral and cognitive features of ASD are associated with pervasive atypicalities in the central nervous system (CNS). To date, the exact mechanisms underlying the pathophysiology of ASD still remain unknown and there is currently no cure or effective treatment for this disorder. Many publications implicated the association of ASD with inflammation, immune dysregulation, neurotransmission dysfunction, mitochondrial impairment and cell signaling dysregulation. This review attempts to highlight evidence of the major pathophysiology of ASD including abnormalities in the brain structure and function, neuroglial activation and neuroinflammation, glutamatergic neurotransmission, mitochondrial dysfunction and mechanistic target of rapamycin (mTOR) signaling pathway dysregulation. Molecular and cellular factors that contributed to the pathogenesis of ASD and how they may affect the development and function of CNS are compiled in this review. However, findings of published studies have been complicated by the fact that autism is a very heterogeneous disorder; hence, we addressed the limitations that led to discrepancies in the reported findings. This review emphasizes the need for future studies to control study variables such as sample size, gender, age range and intelligence quotient (IQ), all of which that could affect the study measurements. Neuroinflammation or immune dysregulation, microglial activation, genetically linked neurotransmission, mitochondrial dysfunctions and mTOR signaling pathway could be the primary targets for treating and preventing ASD. Further research is required to better understand the molecular causes and how they may contribute to the pathophysiology of ASD.

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