scholarly journals 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

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

scholarly journals 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

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii34-ii34
Author(s):  
Nobuyoshi Sasaki ◽  
Koichi Ichimura ◽  
Motoo Nagane ◽  
Arata Tomiyama
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Subcellular Localization ◽  
Human Cancer ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Site Directed Mutagenesis ◽  
Significant Shift ◽  
Wild Type

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.

scholarly journals Programmed cell death 1 expression is associated with inferior survival in patients with primary central nervous system lymphoma

Oncotarget ◽  
2017 ◽  
Vol 8 (50) ◽  
pp. 87317-87328 ◽  
Author(s):  
Hyunsoo Cho ◽  
Se Hoon Kim ◽  
Soo-Jeong Kim ◽  
Jong Hee Chang ◽  
Woo-Ick Yang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Programmed Cell Death ◽  
Central Nervous System Lymphoma ◽  
Programmed Cell Death 1

scholarly journals Clinicopathologic correlates of MYD88 L265P mutation and programmed cell death (PD-1) pathway in primary central nervous system lymphoma

2019 ◽  
Vol 60 (12) ◽  
pp. 2880-2889 ◽  
Author(s):  
Tarsheen K. Sethi ◽  
Alexandra E. Kovach ◽  
Natalie S. Grover ◽  
Li-Ching Huang ◽  
Laura A. Lee ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Nervous System ◽  
Programmed Cell Death ◽  
Central Nervous System Lymphoma ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

scholarly journals Patients with Primary Central Nervous System Lymphoma Have High Levels of Soluble Programmed Cell Death Protein 1 in Their Pretherapeutic Cerebrospinal Fluid

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1334-1334
Author(s):  
Rasmus Svane Ditlev Severinsen ◽  
Marie Beck Enemark ◽  
Julie Bondgaard Mortensen ◽  
Eigil Kjeldsen ◽  
Michael Thorsgaard ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cell Death ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Programmed Cell Death ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
Control Group ◽  
Study Cohort ◽  
Cell Death Protein

Abstract § s hared first authorship; §§ s hared last authorship Primary Central Nervous System Lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma with limited treatment options and severe prognosis. It may display copy number abnormalities of the 9p24.1 locus harboring the programmed cell death protein ligand 1 (PD-L1) gene. Moreover, tumor lesions often overexpress programmed cell death protein 1 (PD-1) as well as its ligands (PD-L1/PD-L2). Soluble forms of these molecules have been demonstrated in serum and plasma, though the biological and clinical significance of these soluble checkpoint proteins is yet unclear. Furthermore, their presence in the cerebrospinal fluid (CSF), particularly in malignant diseases, is largely unexplored. Thus, the aim of our study was to measure the occurrence of soluble PD-1 (sPD-1) in the CSF of PCNSL patients. We measured sPD-1 levels in pretherapeutic plasma and CSF samples from 11 patients with histopathologically confirmed PCNSL of diffuse large B-cell type (DLBCL) and five patients in which the histopathological examination did not confirm the initial clinical and imaging-based suspicion of PCNSL diagnosis (non-PCNSL). All blood and CSF samples were obtained prior to neurosurgical biopsy. Of these five patients, four had reactive non-malignant lesions and one a glioblastoma. Six CSF samples routinely screened for non-malignant neurological disease (e.g. sclerosis) were included as an additional non-PCNSL control group (neuro-screen samples). All samples were handled identically prior to analysis. Soluble PD-1 was measured using an in-house time-resolved immunofluorometric assay (TRIFMA) as previously reported by our group (Mortensen JB et al. Eur J Haematol. 2021 Jul;107:81-91). All samples were analyzed in duplicates. The TRIFMA was validated for freeze/thaw interference and recovery. We found that pretherapeutic CSF sPD-1 levels in PCNSL patients were approximately 10 to 30-fold higher than those of non-PCNSL and neuro-screen patients (p<0,001). The median CSF sPD-1 level for PCNSL was 628 pg/mL, while the corresponding values for the non-PCNSL and neuro-screen subgroups were 48 pg/mL and 19 pg/mL, respectively. Fig. 1a shows the sPD-1 values measured in the three different subsets (PCNSL, non-PCNSL, neuro-screen) of the study cohort. Three PCSNL patients had particularly high sPD-1 values (range: 1642-2194 pg/mL) in their pretherapeutic CSF samples. Interestingly, these three patients all displayed 'high-risk' molecular features, i.e., one case of double-overexpression of bcl-6 and c-Myc and the only two cases of triple-overexpression of bcl-2, bcl-6 and c-Myc. In all 11 PCNSL patients, the DLBCL histology had an activated B-cell like (ABC)/non-germinal center B-cell like (non-GCB) signature. Plasma samples were only available for the PCNSL and non-PCNSL subsets. The median plasma sPD-1 value was 142 pg/mL and 124 pg/mL, respectively. As opposed to non-PCNSL, the CSF sPD-1 levels of PCNSL patients were higher than the paired plasma values (p<0.001; Fig.1b). TRIFMA based measurement of sPD-L1/2 in all available CSF samples and genomic analyses of pretherapeutic PCNSL tissue biopsies are ongoing. At the time of analysis, the median follow-up of the PCNSL cohort was 17 months (range: 1-47) with three deaths observed at 1, 2 and 4 months, respectively. Among the remaining eight patients, six are in continuous 1st complete remission (CR) and two in 2nd CR. Of the six patients in 1st CR, four underwent consolidation with upfront autologous transplant. So far, no significant correlation between CSF sPD-1 and survival has been observed. Despite the limited size of our cohort, we demonstrated that sPD-1 is present and measurable in the CSF of previously untreated PCNSL patients. Moreover, we observed that sPD-1 levels in the pretherapeutic CSF samples from PCNSL were significantly higher than those measured in the non-PCNSL and neuro-screen samples. The PCNSL patients with the most adverse histological features were also the ones with the highest sPD-1 levels in the pretherapeutic CSF. Confirmation of these findings in a larger independent cohort as well as sequential measurements obtained during the course of the disease are warranted. If confirmed, our observations may help to evaluate the usefulness of CSF sPD-1 measurements with regard to disease monitoring as well as checkpoint inhibition strategies in PCNSL. Figure 1 Figure 1. Disclosures Pulczynski: Investigator of a clinical trial (Nordic Lymphoma Group NLG- LBC7(Polar Bear) EudraCT No 2018- 0038 funded by Roche: Research Funding.

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