Genome-Wide Analysis Uncovers Recurrent Alterations in Primary Central Nervous System Lymphomas

Abstract Abstract 420 Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma that is confined to the CNS because of a poorly understood neurotropism. Most of PCNSL (90%) are part of the immune-privileged site-associated DLBCL (IPDLBCL). IPDLBCL consist in late–germinal center or post–germinal center lymphoid cells but that show very distinct characteristics that separate them from systemic DLBCL. It is still a matter of debate whether the PCNSL differ from nodal DLBCL with respect to molecular features and pathogenesis and also if there is a genomic signature specific of PCNSL. Only few genetic studies have been performed in PCNSL, partly due to the rarity of the tumors and the limited amount of available tissue. To gain insight into the genomic basis of PCNSL, we performed an integrated, high-throughput, genomic analysis in 17 immunocompetent, EBV- and HIV- cases. B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and BCL-6. Either frozen samples or formalin fixed embedded paraffin sections from 17 PCNSL were studied by array-based comparative genomic hybridization (aCGH) using Sureprint G3 (1 million probes) array. Massively parallel whole-exome sequencing was performed in 4 of these cases. Additionally, 2 cases were analyzed by mate-pair whole genome sequencing searching for chromosomal breakpoints. Sanger DNA sequencing was used for validation. All cases were characterized by complex genomic aberrations with a median of 21 copy-number abnormalities (CNA, range 10–49), 4 structural abnormalities, 6 frameshift indels and 99 nonsynonymous exonic mutations. Focal deletion affecting CDKN2A (9p21) was the most common CNA, found in 14 of 17 cases (82%); with 6 of these cases (35%) having homozygous deletion. The second most frequent CNA involved the HLA genes (6p21), found in 11 of 17 (65%) cases; 4 of them (23%) with homozygous deletions. We identified recurrent CNA and mutations in several genes previously found in systemic DLBCL. Thus, PRDM1 (BLIMP1) was deleted or mutated in 47% of cases and the translocation IgH-BCL6 was found in 30% of PCNSL. Furthermore, recurrent mutations were found in NF-kB genes CD79B (75%, 3 of 4 cases analyzed), MYD88 (70%, 7 of 10), TNFAIP3 (50%, 2 of 4) and CARD11 (50%, 2 of 4). Additionally, recurrent abnormalities were found in B2M, BCL7A, CD58, CIITA, ETV6, GNA13, PAX5, TMEM30A and TP53. Nevertheless, we identified several recurrent genetic alterations not described in systemic DLBCL. TOX (a regulator of T-cell development) and TBL1XR1 (a negative regulator of the NF-kB and Wnt pathways) were either deleted or mutated in 30% of PNCSL, something not previously described in systemic DLBCL. Additionally, chromosomal breakpoints either in DLGAP1 or DLGAP2 (play a role in neuronal cell signaling) were found in 18% of PCNSL but not in systemic DLBCL. Moreover, mutations in ATM (master controller of cell cycle checkpoint), BAI3 (inhibitor of brain angiogenesis), BTG2 (cell cycle arrest), KDM6B (histone demethylase), PKC family members PRKCD/PRKCDE, genes from the histone cluster, the protocadherin family and the WD repeat domain were found in 10% to 50% of PCNSL. Pathway analysis including the most commonly affected genes in PCNSL showed an enrichment of networks associated with immune response, NF-kB pathway, proliferation, regulation of the apoptosis and lymphocyte differentiation and activation. In summary, we show evidence of a highly complex genome and identified a subset of genes with potential relevance in PCNSL pathogenesis. The genomic profile described here reinforces the existence of a specific molecular signature in PCNSL, thus helping to genetically differentiate this entity from the nodal DLBCL and related lymphomas. Disclosures: Stewart: Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy; Binding site: Consultancy; Millenium: Consultancy; AMGEN: Consultancy; Celgene : Research Funding; Onyx: Research Funding; prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

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The Genomic Landscape Of Primary Central Nervous System Lymphomas

Blood ◽

10.1182/blood.v122.21.504.504 ◽

2013 ◽

Vol 122 (21) ◽

pp. 504-504 ◽

Cited By ~ 1

Author(s):

Esteban Braggio ◽

Brian Patrick O'Neill ◽

Scott Van Wier ◽

Juhi Ojha ◽

Jackline ayres-Silva ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Copy Number ◽

Research Funding ◽

Central Nervous System Lymphoma ◽

Genetic Alterations ◽

Activating Mutations ◽

Genomic Study ◽

Recurrent Mutations ◽

Systemic Dlbcl

Abstract Primary central nervous system lymphoma (PCNSL) is an aggressive and incurable variant of non-Hodgkin lymphoma (NHL) that is confined to the central nervous system. Most PCNSL (90%) are part of the immune-privileged site-associated diffuse large B-cell lymphomas (DLBCL). Unlike nodal DLBCL, only a limited number of genetic studies have been performed in PCNSL, partly due to lack of available tissue specimens. Because of the fragmented knowledge of the genomic basis, it is still a matter of debate whether they differ from systemic DLBCL with respect to their molecular features and pathogenesis and also if there is a CNS specific signature. We performed a comprehensive genomic study in a cohort of 22 immunocompetent (HIV- and EBV-) PCNSL. DNA was extracted from FFPE tissues (N=15) and frozen tissue (N=7). Samples were analyzed using a combination of aCGH (N=18), exome sequencing (N=10), mate-pair genome sequencing (N=2) and targeted sequencing (N=8). We found a complex karyotype with a median of 21 copy-number abnormalities (range 10–47), 6 structural abnormalities, 6 frameshift indels and 67 nonsynonymous mutations. By integrating mutation and copy number data we found a group of genes recurrently mutated and/or deleted in PNCSL. Remarkable findings were the high prevalence of MYD88 activating mutations (L265P/M232T/V217F), found in 69% of cases and the biallelic loss of CDKN2A (60%). A subset of recurrent abnormalities was exclusively found in PCNSL, and not being previously identified in systemic DLBCL. Thus, 11% of PCNSL have biallelic inactivation of TOX (a regulator of T-cell development) and PRKCD (protein kinase C delta), while another 17% of cases show focal monoallelic deletions/mutations in these genes. Finally, recurrent mutations have been identified in ATM, which have not been found in nodal DLBCL. Several other genes affected have been previously identified in nodal DLBCL, such as biallelic loss of TNFAIP3 (16%), PRDM1 (16%), GNA13, TMEM30A, B2M and CD58 (11% each), activating mutations of CD79B (28%) and CARD11 (19%) and translocations of BCL6 (22%). Components of the NF-kB pathways were altered in >90% of PNCSL. Pathway analysis also showed an enrichment of networks associated with immune response, proliferation, regulation of apoptosis and lymphocyte differentiation and activation. Finally, we searched for associations between genetic alterations and clinical outcome. We showed that deletions of 6q21 (PRDM1) and 6q23 (TNFAIP3) were both associated with shorter overall survival (p=0.007 and p=0.03, respectively). In summary, we report a genomic background in PCNSL similar to post-GC DLBCL but reinforcing the existence of a subset of abnormalities specific to PCNSL, suggesting their potential relevance in the disease pathogenesis. Additionally, the results obtained from FFPE samples are encouraging and larger archival tissue collections can now be analyzed in order to complement the still fragmented knowledge we have of the genetic basis of the disease. Disclosures: Stewart: Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Fonseca:Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Patents & Royalties.

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The genomic and transcriptional landscape of primary central nervous system lymphoma

10.1101/2021.07.30.21261280 ◽

2021 ◽

Author(s):

Josefine Radke ◽

Naveed Ishaque ◽

Randi Koll ◽

Zuguang Gu ◽

Elisa Schumann ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Signaling Pathways ◽

Genetic Alterations ◽

Recurrent Mutations ◽

Mutational Hotspots ◽

The Central Nervous System ◽

Transcriptional Landscape ◽

Systemic Dlbcl

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the genomic and transcriptional landscape of PCNSL, we here performed whole-genome and transcriptome sequencing and integrative analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL and matched controls. The results were compared to an independent validation cohort of 31 FFPE CNSL specimens (PCNSL, n = 19; SCNSL, n = 9; EBV+ CNSL, n = 3) as well as 39 FL and 36 systemic DLBCL cases outside the CNS. Somatic genomic alterations in PCNSL mainly affect the JAK-STAT, NFkB, and B-cell receptor signaling pathways, with hallmark recurrent mutations including MYD88 L265P (67%) and CD79B (63%), CDKN2A deletions (83%) and also non-coding RNA genes such as MALAT1 (70%), NEAT (60%), and MIR142 (80%). Kataegis events, which affected 15 of 50 identified driver genes and 21 of the top 50 mutated ncRNAs, played a decisive role in shaping the mutational repertoire of PCNSL. Compared to systemic DLBCL, PCNSLs exhibited significantly more focal deletions in 6p21 targeting the HLA-D locus that encodes for MHC class II molecules as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis (SBS1, ID1 and ID2) were significantly enriched in PCNSL (SBS1: p = 0.0027, ID1/ID2: p < 1x10-4). Furthermore, TERT gene expression was significantly higher in PCNSL compared to ABC-DLBCL (p = 0.027). Although PCNSL share many genetic alterations with systemic ABC-DLBCL in the same signaling pathways, transcriptome analysis clearly distinguished both into distinct molecular subtypes. EBV+ CNSL cases may be distinguished by lack of recurrent mutational hotspots apart from IG and HLA-DRB loci.

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Genetic Basis of Primary Central Nervous System Lymphoma

Blood ◽

10.1182/blood.v126.23.2687.2687 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2687-2687

Author(s):

Kenichi Yoshida ◽

Rie Nakamoto-Matsubara ◽

Kenichi Chiba ◽

Yusuke Okuno ◽

Nobuyuki Kakiuchi ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

B Cell ◽

Copy Number ◽

Genetic Basis ◽

Snp Array ◽

Central Nervous System Lymphoma ◽

Genetic Alterations ◽

Targeted Sequencing ◽

Systemic Dlbcl

Abstract Introduction Primary central nervous system lymphoma (PCNSL) is a rare subtype of non-Hodgkin lymphoma, of which approximately 95% are diffuse large B-cell lymphomas (DLBCLs). Despite the substantial development of intensive chemotherapy during the past two decades, overall clinical outcome of PCNSL has been poorly improved especially in elderly and so has been our knowledge about the molecular pathogenesis of PCNSL, in terms of driver alterations that are relevant to the development of PCNSL. Method To delineate the genetic basis of PCNSL pathogenesis, we performed a comprehensive genetic study. We first analyzed paired tumor/normal DNA from 35 PCNSL cases by whole-exome sequencing (WES). Significantly mutated genes identified by WES and previously known mutational targets in PCNSL and systemic DLBCL were further screened for mutations using SureSelect-based targeted deep sequencing (Agilent) in an extended cohort of PCNSL cases (N = 90). Copy number alterations (CNAs) have been also investigated using SNP array-karyotyping (N =54). We also analyzed WES and SNP array data of systemic DLBCL cases (N = 49) generated by the Cancer Genome Atlas Network (TCGA) to unravel the genetic difference between PCNSL and systemic DLBCL. Results The mean number of nonsynonymous mutations identified by WES was 183 per sample, which was comparable to the figure in systemic DLBCL and characterized by frequent somatic hypermutations (SHMs) involving non-Ig genes. A higher representation of C>T transition involving CpG dinucleotides and hotspot mutations within the WRCY motif targeted by SHM further suggested the involvement of activation-induced cytidine deaminase (AID) in the pathogenesis of PCNSL. We found 12 genes significantly mutated in PCNSL (q < 0.1), including MYD88, PIM1, HLA-A, TMEM30A, B2M, PRDM1, UBE2A, HIST1H1C, as well as several previously unreported mutational targets in systemic DLBCL or PCNSL, such as SETD1B, GRB2, ITPKB, EIF4A2. Copy number analysis identified recurrent genomic segments affected by focal deletions (N = 27) and amplifications (N = 10), most of which included driver genes targeted by recurrent somatic mutations or known targets of focal CNAs such as CDKN2A and FHIT. Subsequent targeted sequencing finally identified a total of 107 significantly mutated genes, of which 43 were thought to be targeted by SHM according to their mutational signature and genomic distribution. Most cases with PCNSL (98%) had mutations and CNAs involving genes that are relevant to constitutive NF-KB/Toll-like receptor (TLR)/BCR activity, including those in MYD88 (80%), CD79B/A (60%), CARD11 (18%), TNFAIP3 (26%), GRB2 (24%) and ITPKB (23%). Genetic alterations implicated in escape from immunosurveillance were also frequently identified in as many as 76% of cases. Mutations of HLA-B (64%), HLA-A (36%), HLA-C (28%), B2M (14%) and CD58 (12%) were commonly detected in addition to CNAs in 6p21.32 (HLA class II), 1p13.1 (CD58) and 15q15.2 (B2M), suggesting the importance of immune escape in the pathogenesis of PCNSL. SHMs were also seen in most cases (98%), which affected not only known targets of AID including PIM1, IGLL5 and BTG2 but also previously unreported genes involved in cell proliferation, apoptosis, or B cell development. The pattern of frequently mutated genes in PNCSL was more uniform compared with that in systemic DLBCL, and similar to that found in the activated B cell subtype of DLBCL (ABC-DLBCL), which was in accordance with the previous report of immunophenotypic analysis of PCNSL. On the other hand, mutations of HLA class I genes (HLA-B, HLA-A) were more frequently mutated in PCNSL compared with ABC-type DLBCL. Conclusion WES, SNP array karyotyping and follow-up targeted sequencing of a large cohort of PCNSL cases revealed the genetic landscape of PCNSL, which were more homogeneous than that of systemic DLBCL, and thought to be involved in activation of constitutive NF-KB/TLR/BCR signaling, escape from immunosurveillance, as well as highly frequent SHMs. Disclosures No relevant conflicts of interest to declare.

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Nivolumab (Anti-PD1) Therapy for Relapsed/ Refractory Primary Central Nervous System Lymphoma and Primary Testicular Lymphoma

Blood ◽

10.1182/blood.v128.22.930.930 ◽

2016 ◽

Vol 128 (22) ◽

pp. 930-930 ◽

Cited By ~ 2

Author(s):

Lakshmi Nayak ◽

Fabio Iwamoto ◽

Ann S. LaCasce ◽

Srinivasan Mukundan ◽

Margaretha G M Roemer ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

T Cell ◽

Research Funding ◽

Central Nervous System Lymphoma ◽

Genetic Alterations ◽

High Dose ◽

Cns Relapse ◽

Testicular Lymphoma ◽

Primary Testicular Lymphoma

Abstract Background: Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare and aggressive extranodal non-Hodgkin lymphomas with shared molecular features and a poor prognosis. PCNSL is currently treated with high-dose methotrexate (HD-MTX) based induction chemotherapy. Younger patients who are healthy and eligible for consolidation treatment are considered for whole brain radiation (WBRT) or high-dose chemotherapy with autologous stem-cell transplant (ASCT). Despite this, nearly 50% of patients with PCNSL relapse within 2 years of diagnosis and one third of patients have primary refractory disease. PTL is treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, almost 50% of patients with PTL progress after induction treatment, frequently with CNS or contralateral testicular involvement. Treatment options are limited for patients with recurrent and refractory PCNSL or PTL, and the majority of patients ultimately die of their disease. We recently identified frequent 9p24.1/ PD-L1(CD274)/ PD-L2 (PDCD1LG2) copy number alterations and additional translocations in PCNSL and PTL (Chapuy and Roemer et al Blood 2016; 127:869-81). These genetic alterations are associated with increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. Activation of PD-1 signaling by PD-L1 or PD-L2 binding leads to a reversible state of T-cell "exhaustion" characterized by decreased T-cell receptor signaling, reduced T-cell proliferation and survival, perturbed metabolism and altered transcription factor expression. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations such as classical Hodgkin's lymphoma prompted us to test the efficacy of this approach in PCNSL and PTL. Patients and Methods: We treated 5 patients with recurrent/refractory PCNSL and PTL with off-label Nivolumab, a humanized IgG4 monoclonal antibody checkpoint inhibitor that targets PD-1 and blocks binding by PD-L1 or PD-L2. Median age was 64 (range, 54-85) years with a median Karnofsky Performance Score (KPS) of 70 (40-80) %. Four patients had multiply recurrent disease (3 patients with PCNSL and 1 patient with PTL and CNS relapse); 1 patient had primary refractory PCNSL. All patients had been treated with standard of care treatments and had no other available options. Prior therapies included HD-MTX based chemotherapy, pemetrexed, high-dose cytarabine, WBRT and thiotepa-based chemotherapy followed by ASCT. All patients signed informed consent and were treated with nivolumab at 3mg/kg intravenously every 2 weeks. Only 1 patient received corticosteroids (dexamethasone 2mg daily) during initial nivolumab treatment; steroids were rapidly tapered and discontinued in 4 weeks. Additionally, 1 patient received 3 doses of rituximab and 2 others received WBRT. All patients had objective radiographic responses to treatment with nivolumab, including 4 complete responses and 1 partial response. The patient with CNS relapse from PTL had complete radiographic resolution of CNS abnormalities with persistent intraocular disease that required vitrectomy. All responses were confirmed at repeat restaging. The median number of nivolumab treatments to objective radiographic response was 3 (range, 2-4). The 4 patients who were symptomatic at the initiation of nivolumab therapy had complete or near-complete resolution of neurologic signs/symptoms and a marked improvement in KPS. All patients are alive and remain progression-free at this time. Four patients continue to receive treatment. The median progression-free survival is 9 (range, 7-11) months. Conclusion: Our pilot series indicates that nivolumab is active in primary refractory and relapsed/refractory PCNSL and PTL with CNS relapse. Based on our preclinical molecular data and these pilot clinical results, a multi-institutional phase 2 open-label, single-arm trial of nivolumab in recurrent and refractory PCNSL and PTL patients (CA209-647) is scheduled to open shortly. Disclosures LaCasce: Forty Seven: Consultancy; Seattle Genetics: Consultancy. Armand:Infinity Pharmaceuticals: Consultancy; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sequenta Inc: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Shipp:Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.

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Central Nervous System Complications after Allogeneic Hematopoietic Stem Cell Transplantation: The Role of Calcineurin Inhibitors

Blood ◽

10.1182/blood-2018-99-114977 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4601-4601

Author(s):

Elisa Sala ◽

Stephanie von Harsdorf ◽

Verena Wais ◽

Thanh Mai Anne Nguyen ◽

Raphael Beck ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Research Funding ◽

Calcineurin Inhibitors ◽

Neurological Manifestations ◽

Hematopoietic Stem ◽

Gvhd Prophylaxis ◽

Prophylaxis Therapy

Abstract Introduction Despite its curative potential, the outcome after allogeneic hematopoietic stem cell transplantation (SCT) strongly depends on transplant-related mortality. Neurological complications, especially those affecting the central nervous system (CNS), are often associated with a significant rate of morbidity. Commonly used immunosuppressive drugs are calcineurin inhibitors (CNI) such as cyclosporinA (CsA) and tacrolimus (TAC) which are associated with an increased risk of neurotoxicity. So far no direct comparison between CsA and TAC has been performed to identify the better option in terms of "neurologic tolerability" in the setting of SCT. Patients and Methods We performed a retrospective analysis of consecutive patients (pts) who underwent SCT for different hematological malignancies and developed one or more CNS complications between 1999 and 2018 at the University Hospital of Ulm (Germany) and received CsA or TAC as Graft versus Host Disease (GvHD) prophylaxis/therapy. During post transplant follow up, in case of neurological manifestations, neurological evaluation, brain imaging (CT-scan or MRI), electroencephalography and, if necessary, a lumbar puncture (including microbiological analysis) were performed. Results We identified 60 out of 1256 pts who experienced a total of 79 CNS complications. Pts' characteristics are listed in Table 1. Seventy-four of 79 (94%) complications occurred in pts receiving CNI (n=58/60 pts): 51/74 (69%) were detected during or after TAC administration, while in 23/74 cases (31%) CsA was used. No statistically significant differences were observed in the two subgroups with regard to conditioning regimen (myeloablative vs reduced intensity), donor type (matched related vs matched unrelated vs mismatched related), and incidence of severe GvHD (both acute and chronic). In both cohorts early complications (within 1 month after SCT) were mostly represented by vascular events and metabolic encephalopathy (sepsis or chemotherapy-related). As intermediate complications (2-6 months after SCT) we observed a trend towards increased infections of herpes encephalitis in the TAC cohort (p=0.08), CNI-neurotoxicity and CNS symptoms due to severe transplant-associated microangiopathy (TMA). As late effects (>1 year (y) after SCT) we detected secondary CNS neoplasms, CNS relapse or neurologic effects of chronic GvHD. Comparing the time of onset of all complications, we observed a median time of 6 months after SCT in the TAC-cohort (range: day -1 - 13y) and of 11 months in the CsA-cohort (range: day 0 - 4y). The frequency of the different types of CNS complications was similar in the two cohorts with exception for the occurrence of neurological manifestations related to TMA (Figure 1), which was statistically significant higher (p=0.01) in pts receiving TAC. These changes were reversible in 33% of cases (4/12) after discontinuation of TAC (which, at the time of TMA onset, was within or below the therapeutic ranges in 91% of cases) or after specific treatment (e.g. Eculizumab, plasma exchange). Conclusions Our data suggest a possible increment of neurologic complications in pts undergoing GvHD prophylaxis/therapy with TAC, especially related to the development of severe TMA, which is known to promote mental status changes. Although these findings need to be further explored and validated in larger prospective cohorts, they could have clinical relevance, such as avoiding TAC in pts at high risk of developing TMA as well as a stricter TMA monitoring in pts undergoing GvHD prophylaxis with TAC to minimize the development of severe TMA forms with neurological involvement. Disclosures Döhner: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; AROG Pharmaceuticals: Research Funding; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding.

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mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system

eLife ◽

10.7554/elife.14908 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 48

Author(s):

Linqing Miao ◽

Liu Yang ◽

Haoliang Huang ◽

Feisi Liang ◽

Chen Ling ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Axon Regeneration ◽

Nodal Point ◽

Mtor Signaling ◽

Negative Regulator ◽

Molecular Dissection ◽

Parallel Pathways ◽

Downstream Effectors ◽

The Central Nervous System

Injured mature CNS axons do not regenerate in mammals. Deletion of PTEN, the negative regulator of PI3K, induces CNS axon regeneration through the activation of PI3K-mTOR signaling. We have conducted an extensive molecular dissection of the cross-regulating mechanisms in axon regeneration that involve the downstream effectors of PI3K, AKT and the two mTOR complexes (mTORC1 and mTORC2). We found that the predominant AKT isoform in CNS, AKT3, induces much more robust axon regeneration than AKT1 and that activation of mTORC1 and inhibition of GSK3β are two critical parallel pathways for AKT-induced axon regeneration. Surprisingly, phosphorylation of T308 and S473 of AKT play opposite roles in GSK3β phosphorylation and inhibition, by which mTORC2 and pAKT-S473 negatively regulate axon regeneration. Thus, our study revealed a complex neuron-intrinsic balancing mechanism involving AKT as the nodal point of PI3K, mTORC1/2 and GSK3β that coordinates both positive and negative cues to regulate adult CNS axon regeneration.

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The Cell Cycle in the Central Nervous System

10.1007/978-1-59745-021-8 ◽

2006 ◽

Keyword(s):

Cell Cycle ◽

Central Nervous System ◽

Nervous System ◽

The Central Nervous System

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Adult Neurogenesis and Central Nervous System Cell Cycle Analysis

Contemporary Neuroscience - The Cell Cycle in the Central Nervous System ◽

10.1007/978-1-59745-021-8_25 ◽

2008 ◽

pp. 331-358 ◽

Cited By ~ 1

Author(s):

Amelia J. Eisch ◽

Chitra D. Mandyam

Keyword(s):

Cell Cycle ◽

Central Nervous System ◽

Nervous System ◽

Adult Neurogenesis ◽

Cell Cycle Analysis ◽

Central Nervous System Cell ◽

System Cell

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Conditional Mutation of Rb Causes Cell Cycle Defects without Apoptosis in the Central Nervous System

Molecular and Cellular Biology ◽

10.1128/mcb.23.3.1044-1053.2003 ◽

2003 ◽

Vol 23 (3) ◽

pp. 1044-1053 ◽

Cited By ~ 89

Author(s):

D. MacPherson ◽

J. Sage ◽

D. Crowley ◽

A. Trumpp ◽

R. T. Bronson ◽

...

Keyword(s):

Cell Cycle ◽

Central Nervous System ◽

Nervous System ◽

Muscle Development ◽

Brain Size ◽

Targeted Disruption ◽

Show Evidence ◽

The Central Nervous System ◽

P53 Activation ◽

Phase Entry

ABSTRACT Targeted disruption of the retinoblastoma gene in mice leads to embryonic lethality in midgestation accompanied by defective erythropoiesis. Rb −/− embryos also exhibit inappropriate cell cycle activity and apoptosis in the central nervous system (CNS), peripheral nervous system (PNS), and ocular lens. Loss of p53 can prevent the apoptosis in the CNS and lens; however, the specific signals leading to p53 activation have not been determined. Here we test the hypothesis that hypoxia caused by defective erythropoiesis in Rb-null embryos contributes to p53-dependent apoptosis. We show evidence of hypoxia in CNS tissue from Rb −/− embryos. The Cre-loxP system was then used to generate embryos in which Rb was deleted in the CNS, PNS and lens, in the presence of normal erythropoiesis. In contrast to the massive CNS apoptosis in Rb-null embryos at embryonic day 13.5 (E13.5), conditional mutants did not have elevated apoptosis in this tissue. There was still significant apoptosis in the PNS and lens, however. Rb −/− cells in the CNS, PNS, and lens underwent inappropriate S-phase entry in the conditional mutants at E13.5. By E18.5, conditional mutants had increased brain size and weight as well as defects in skeletal muscle development. These data support a model in which hypoxia is a necessary cofactor in the death of CNS neurons in the developing Rb mutant embryo.

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