ML-12 MECHANISMS OF CELL DEATH INHIBITION THROUGH CHANGE IN SUBCELLULAR LOCALIZATION OF PIM-1 BY PIM1 GENE MUTATION RECURRENTLY FOUND IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

Abstract BACKGROUNDS In a study of Next Generation Sequencing in primary central nervous system lymphoma (PCNSL), we have previously reported several mutations of high frequency, in comparison with systemic diffuse large B cell lymphoma (DLBCL)s. Consequences of these specific mutations in PCNSL are unknown. In this study, we have analyzed the functional consequence of mutations in the PIM1 gene, observed in 100% of PCNSL patients, which encodes a serine/threonine kinase and is known to drive tumorigenesis in several malignancies. METHODS Four most frequent mutations of PIM1 in PCNSL, S77N, K115N, P216S, L275F, were chosen from our previous study, and each mutant was generated by site directed mutagenesis in PIM1 cDNA cloned in an expression vector. Resulting vectors were transiently transfected into human cancer cell lines. Functional studies were carried out using various biochemical methods. RESULTS Among the four mutants, increased phosphorylation of BCL-2 associated death promoter (BAD) at Ser112, which is a phosphorylation target of Pim-1, was observed by expression of K115N mutant compared with wild type PIM1 in Hela and Nagai cells expressing endogeneous BAD. Decreased cell death under campthothecin treatment was also observed in K115N mutant expressing Nagai cells compared with wild type PIM1-expressed cells. We also observed a significant shift in subcellular localization of Pim-1 carrying K115N mutant; from the nucleus, main sublocalization for wild type Pim-1, into the cytosol determined by immunocytochemistry and immunoblotting of nuclear and cytosolic fraction of the cells. Augmented cytosolic localization of Pim-1 carrying K115N mutant was suppressed by inhibition of glycosylation. DISCUSSION It is suggested that PIM1 K115N mutant may drive chemoresistance through increased BAD phosphorylation that suppresses cell death compared with wild-type PIM1 through modification of its subcellular localization, which might be regulated by its glycosylation status.

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CSIG-31. MUTATION OF PIM1 GENE IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA INHIBITS CELL DEATH THROUGH CHANGE IN SUBCELLULAR LOCALIZATION OF PIM-1 AND INCREASE OF BAD PHOSPHORYLATION

Neuro-Oncology ◽

10.1093/neuonc/noy148.197 ◽

2018 ◽

Vol 20 (suppl_6) ◽

pp. vi49-vi50

Author(s):

Nobuyoshi Sasaki ◽

Koichi Ichimura ◽

Motoo Nagane ◽

Arata Tomiyama

Keyword(s):

Central Nervous System ◽

Cell Death ◽

Nervous System ◽

Subcellular Localization ◽

Central Nervous System Lymphoma

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MUTATION OF PIM1 GENE IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA INHIBITS CELL DEATH THROUGH CHANGE IN SUBCELLULAR LOCALIZATION OF Pim-1 AND INCREASE OF BAD PHOSPHORYLATION

Hematological Oncology ◽

10.1002/hon.7_2631 ◽

2019 ◽

Vol 37 ◽

pp. 345-345

Author(s):

N. Sasaki ◽

K. Ichimura ◽

M. Nagane ◽

A. Tomiyama

Keyword(s):

Central Nervous System ◽

Cell Death ◽

Nervous System ◽

Subcellular Localization ◽

Central Nervous System Lymphoma

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

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200517112252 ◽

2020 ◽

Vol 19 (3) ◽

pp. 165-173

Author(s):

Xiaowei Zhang ◽

Yuanbo Liu

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Signaling Pathway ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Mtor Signaling ◽

Mtor Signaling Pathway ◽

Antitumor Effects ◽

Term Survival

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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Treatment of secondary central nervous system involvement in systemic aggressive B cell lymphoma using R-MIADD chemotherapy: a single-center study

Chinese Neurosurgical Journal ◽

10.1186/s41016-021-00238-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yuchen Wu ◽

Xuefei Sun ◽

Xueyan Bai ◽

Jun Qian ◽

Hong Zhu ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Central Nervous System Involvement ◽

Central Nervous System Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

High Dose ◽

Cns Involvement ◽

The Central Nervous System ◽

Secondary Central Nervous System

Abstract Background Secondary central nervous system lymphoma (SCNSL) is defined as lymphoma involvement within the central nervous system (CNS) that originated elsewhere, or a CNS relapse of systemic lymphoma. Prognosis of SCNSL is poor and the most appropriate treatment is still undetermined. Methods We conducted a retrospective study to assess the feasibility of an R-MIADD (rituximab, high-dose methotrexate, ifosfamide, cytarabine, liposomal formulation of doxorubicin, and dexamethasone) regimen for SCNSL patients. Results Nineteen patients with newly diagnosed CNS lesions were selected, with a median age of 58 (range 20 to 72) years. Out of 19 patients, 11 (57.9%) achieved complete remission (CR) and 2 (10.5%) achieved partial remission (PR); the overall response rate was 68.4%. The median progression-free survival after CNS involvement was 28.0 months (95% confidence interval 11.0–44.9), and the median overall survival after CNS involvement was 34.5 months. Treatment-related death occurred in one patient (5.3%). Conclusions These single-centered data underscore the feasibility of an R-MIADD regimen as the induction therapy of SCNSL, further investigation is warranted.

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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 LYMPHOMAS

Romanian Journal of Neurology ◽

10.37897/rjn.2015.2.3 ◽

2015 ◽

Vol 14 (2) ◽

pp. 77-84

Author(s):

Adriana Octaviana Dulamea ◽

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Treatment Strategies ◽

Central Nervous System Lymphoma ◽

B Cell Lymphoma ◽

Diagnostic Methods ◽

Hematopoietic Stem ◽

Whole Brain Radiation ◽

Author Review ◽

Immunocompetent Patients

Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin B-cell lymphoma with characteristic clinical behavior, biological features and poor prognosis despite complex treatment. PCNSL has a median survival of 17 to 45 months in immunocompetent patients, and only 20-30% of cases can be cured successfully. Clinical outcome has improved since the advances in combination chemotherapy protocols, addition of whole brain radiation therapy, encouraging responses of rituximab administration in refractory PCNSL and autologous hematopoietic stem-cell transplantation as consolidative therapy. The author review the recent data on pathogenesis, diagnostic methods and treatment strategies of PCNSL in immunocompetent patients.

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