scholarly journals SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Tao Wang ◽  
Wenqin Yue ◽  
Gusheng Tang ◽  
Mingyu Ye ◽  
Jiechen Yu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Cell Lymphoma ◽  
Proliferation Index ◽  
Acute Myelocytic Leukemia ◽  
Chemotherapy Response ◽  
Missense Mutations ◽  
Mantle Cell ◽  
Samhd1 Expression

SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (p = 0.023) and shorter overall survival (p = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an in vitro study using the siRNA technique. Silencing the SAMHD1 gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with SAMHD1 knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the SAMHD1 gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.

scholarly journals CircCDYL Serves as a New Biomarker in Mantle Cell Lymphoma and Promotes Cell Proliferation

2019 ◽  
Vol Volume 11 ◽  
pp. 10215-10221 ◽  
Author(s):  
Mei Mei ◽  
Yingjun Wang ◽  
Qilong Wang ◽  
Yueyao Liu ◽  
Wenting Song ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mantle Cell

scholarly journals p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis

Blood ◽  
1996 ◽  
Vol 87 (10) ◽  
pp. 4302-4310 ◽  
Author(s):  
TC Greiner ◽  
MJ Moynihan ◽  
WC Chan ◽  
DM Lytle ◽  
A Pedersen ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Median Survival ◽  
Poor Prognosis ◽  
Denaturing Gradient Gel Electrophoresis ◽  
Cell Lymphoma ◽  
P53 Protein ◽  
Prognostic Significance ◽  
Missense Mutations ◽  
P53 Mutations ◽  
Mantle Cell

Mutations of the p53 tumor suppressor gene have been described in several subtypes of non-Hodgkin's lymphoma, but the incidence of p53 mutations in mantle cell lymphoma (MCL) is unknown. We hypothesized that cases of MCL with a variant or high-grade cytology would have a higher likelihood of p53 mutations than typical MCL. We were also interested in the prognostic significance of p53 mutations in MCL. Therefore, a series of 53 well-characterized cases of MCL with DNA from 62 tissue samples were analyzed by the polymerase chain reaction with denaturing gradient gel electrophoresis for exons 5–8 of p53. Immunoperoxidase studies with the antibody DO-7 to p53 protein were also performed on frozen sections. We found mutations of the p53 gene in 8 of the 53 cases (15%) of MCL. Missense mutations predominated, and 50% of the mutations occurred at known p53 hotspot codons. Of 21 cases with variant cytology (ie, anaplastic or blastic), 6 (28.6%) had p53 mutations as compared with only 2 of 32 cases (6.3%) with typical MCL cytology (P = .05), and p53 mutations preceded the development of variant cytology in 2 patients. Overexpression of p53 protein was observed in 6 of the 8 cases (75%) with p53 mutations and in none of the 45 wild-type cases. The median survival of the cases with mutant p53 was only 1.3 years (all died), whereas the median survival of cases with germline p53 was 5.1 years (P = .023). These results suggest that mutations of p53 may be one mechanism involved in the development of variant forms of MCL and indicate that p53 mutations in MCL predict a poor prognosis.

Induction of Apoptosis in Jeko-1 Mantle Cell Lymphoma Cell Line by Resveratrol: A Proteomic Analysis

2008 ◽  
Vol 7 (7) ◽  
pp. 2670-2680 ◽  
Author(s):  
Daniela Cecconi ◽  
Alberto Zamò ◽  
Alice Parisi ◽  
Elena Bianchi ◽  
Claudia Parolini ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Proteomic Analysis ◽  
Cell Lymphoma ◽  
Lymphoma Cell ◽  
Lymphoma Cell Line ◽  
Mantle Cell Lymphoma Cell ◽  
Mantle Cell ◽  
Induction Of Apoptosis

Truncations in CCND1 mRNA 3′ UTR Alters microRNA Regulation in Mantle Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3184-3184
Author(s):  
Robert W. Chen ◽  
Lynne Bemis ◽  
Carol Amato ◽  
Birks Diane ◽  
Myint Han ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Expression ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Cell Lymphoma ◽  
Regulation Of Gene Expression ◽  
Proliferative Potential ◽  
Transcriptional Level ◽  
Cell Cycle Regulator ◽  
Mantle Cell

Abstract Mantle Cell Lymphoma (MCL) represents only 5–10% of all non-Hodgkins lymphomas, making it an uncommon but difficult form of lymphoma to treat. It has a poor prognosis among the B cell lymphomas with median survival of three years. The genetic hallmark of MCL is the t(11,14) translocation causing amplification of cyclin D1 (CCND1), a known cell cycle regulator which is overexpressed in many other cancers. MicroRNAs (miRNA) are a new class of abundant small RNAs that play important regulatory roles at the post transcriptional level. They act by binding to the 3′ untranslated region (UTR) of mRNAs and block either their translation or initiate their degradation. Recent reports have shown truncations in the CCND1 3′ UTR occur in MCL and indicate a worse prognosis. We hypothesized that truncations in 3′ UTR of CCND1 alter it’s regulation by microRNAs. Based on bioinformatics, we identified microRNA 16 with putative docking sites in the 3′UTR of CCND1. Mir-16 has been implicated as a cell cycle regulator. We identified 2 cell lines (Jeko-1 and Z138) with truncations in CCND1 3′ UTR and demonstrated increased CCND1 mRNA expression by qRT-PCR, increased protein expression by western blot, and higher proliferative potential by cell cycle. We prepared a reporter construct by ligating the full length 3′ UTR of CCND1 to GFP. We then co-transfected this construct with mimics of mir-16 into a cancer cell line and demonstrated downregulation of CCND1 protein expression by flow cytometry. In the MCL cell line Granta-519 with non-truncated CCND1, transfection with mimics of mir-16 deminstrated decreased expression of CCND1 mRNA. These studies suggest that the overexpression of CCDN1 In MCL may result from altered regulation of gene expression from loss of a miRNA regulatory site and may give new clues into the patho-biology of this disease and insights into possible new therapies.

Combined Epigenetic Therapy with the Novel Histone Methyl Transferase EZH2 Inhibitor 3-Deazaneplanocin and Histone Deacetylase Inhibitor Panobinostat Exerts Synergistic Activity against Human Mantle Cell Lymphoma Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3622-3622
Author(s):  
Warren Fiskus ◽  
Yongchao Wang ◽  
Anand Jillella ◽  
Pace Johnston ◽  
Rajeshree Joshi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mantle Cell Lymphoma ◽  
Histone Deacetylase ◽  
Cell Lymphoma ◽  
Parp Cleavage ◽  
Epigenetic Therapy ◽  
Synergistic Activity ◽  
Gene Promoters ◽  
Core Proteins ◽  
Mantle Cell

Abstract Lysine specific histone methylation and deacetylation and DNA hypermethylation are involved in the epigenetic silencing of tumor suppressor genes (TSG), e.g., p16 and JunB. The multi-protein complex PRC (polycomb repressive complex) 2 that contains the three core proteins EZH2, SUZ12 and EED, has intrinsic histone methyltransferase (HMTase) activity. This is mediated by the SET domain of EZH2, which induces tri-methylation (3Me) of lysine (K)-27 on histone H3, as well as promotes cell proliferation and aggressiveness of neoplastic cells. EZH2 is preferentially overexpressed in proliferating but not resting Mantle Cell Lymphoma (MCL) cells. In the present studies we demonstrate that treatment with the S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin A (DZNep) dose-dependently (500 nM to 2.0 uM) depletes EZH2, SUZ12 and EED levels, as well as inhibits 3Me K27 on H3 while inducing K27 H3 acetylation. DZNep treatment also induces the levels of p21, p27, JunB and FBXO32, while depleting cyclin D1 and cyclin E levels in the cultured human MCL Jeko-1, MO2058 and Z138 cells and in primary patient-derived MCL cells. Treatment with DZNep induces PARP cleavage activity of the caspases and apoptosis in the cultured and primary MCL cells. DZNep promoted proteasomal degradation of EZH2 and SUZ12, since co-treatment with bortezpmib significantly restored EZH2 and SUZ12 levels in the MCL cells. We had previously reported that treatment with the pan-histone deacetylase (HDAC) inhibitor panobinostat (PS) (LBH589, Novartis Pharmaceutical Corp) depletes the levels of EZH2, SUZ12 and EED in cultured and primary AML cells (Mol Cancer Ther.2006; 5:3096). Within the PRC2 complex, EZH2 bound and recruited the DNA methyltransferases DNMT1, and treatment with PS also disrupted the interaction of EZH2 with DNMT1, attenuated DNMT1 levels and its binding to the EZH2-targeted gene promoters, e,g, JunB. Here, we also demonstrate that, PS treatment depletes DNMT1 levels and induces JunB levels in cultured MCL cells. As compared to treatment with either agent alone, co-treatment with DZNep and PS caused more depletion of EZH2 and SUZ12, but not of DNMT1, more induction of JunB, p21 and p27, as well as synergistically induced apoptosis of cultured MCL cells (combination indices < 1.0). Taken together, these findings indicate that DZNep and PS mediated targeting of EZH2 and the PRC2 complex is an effective epigenetic therapy of MCL, which also results in undermining several molecular determinants of MCL cell proliferation and survival. Additionally, combined epigenetic therapy with DZNep and PS exerts synergistic in vitro activity against human MCL cells, suggesting that this combination may be a promising novel treatment for MCL.

FTY720 Demonstrates Promising in-Vitro and in-Vivo Pre-Clinical Activity by Down-Modulation of Cyclin D1 and Pakt in Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3728-3728
Author(s):  
Lapo Alinari ◽  
Qing Liu ◽  
Ching-Shih Chen ◽  
Fengting Yan ◽  
James T Dalton ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Cell Lymphoma ◽  
Tumor Burden ◽  
Time Dependent ◽  
Control Group ◽  
Mantle Cell

Abstract Abstract 3728 Poster Board III-664 Over-expression of Cyclin D1 and constitutive phosphorylation of Akt has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Here we describe FTY720 (fingolimod), an immunosuppressive agent currently being explored in phase III studies in renal transplantation and multiple sclerosis patients, to mediate time- and dose-dependent cell death in primary MCL cells (6 patients) and MCL cell lines, Jeko and Mino. FTY720-induced apoptosis was associated with reactive oxygen species (ROS) generation, Bax up-regulation but not associated with caspase 3 activation in MCL. FTY720 treatment resulted in time-dependent down-modulation of Cyclin D1 and phospho Akt (p-Akt) protein level, two critical disease-relevant molecules in the pathogenesis of MCL. Consistent with the modulation of Cyclin D1, FTY720-induced cell cycle arrest with accumulation of cells in G0/G1 and G2/M phases of the cell cycle with concomitant decrease in S phase entry. Importantly, FTY720 treatment was also associated with a time-dependent phospho Erk (p-Erk) induction in Mino and Jeko cells. To determine the in vivo efficacy of FTY720, we developed a preclinical, in vivo xenograft model of human MCL where MCL cell lines (Jeko, Mino and SP53) were engrafted into severe combined immune deficient (SCID) mice. Cell dose titration trials identified 4 × 107 Mino or Jeko cells injected intravenously via tail vein to result in consistent engraftment and fatal tumor burden in all mice. All mice engrafted with 4 × 107 Jeko cells developed a disseminated disease within 3 weeks and had a median survival of 28 days (compared to 43 days for Mino and 51 days for SP53). Because the Jeko cell line was established from the peripheral blood of a patient with blastic variant MCL and demonstrated a more resistant phenotype to several immuno-chemoterapeutic compounds, this cell line was chosen to create a more stringent in vivo preclinical model. SCID mice were treated with the monoclonal antibody TMβ1 to deplete murine NK cells, engrafted with 4 × 107 Jeko cells and observed daily for signs of tumor burden. Ten mice/group were treated starting at day 15 post-engraftment with intraperitoneal injection of 100 μl of saline or FTY720 (5 mg/kg resuspended in 100 μl of saline), every day, for two weeks. The median survival for FTY720-treated mice (N=10) was 38 days (95% CI:30-39) compared to 26.5 days (95% CI: 26-27 days) for the control group mice (N=10). The results from the log-rank test indicated an overall statistical significant difference in survival functions between the FTY720 treatment and the control group (p=0.001). These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant the further investigation of FTY720 in combination with other agents in clinical trials treating patients with MCL. Disclosures: No relevant conflicts of interest to declare.

Whole Transcriptome Sequencing Reveals Recurrent NOTCH1 Mutations in Mantle Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 436-436 ◽  
Author(s):  
Robert Kridel ◽  
Barbara Meissner ◽  
Sanja Rogic ◽  
Merrill Boyle ◽  
Adele Telenius ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
The Other ◽  
Mantle Cell ◽  
Whole Transcriptome ◽  
Notch1 Mutations

Abstract Abstract 436 Background: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma that is characterized by the hallmark t(11;14)(q13;q32) translocation, as well as a high number of secondary chromosomal alterations. Further, a small number of genes such as TP53, ATM and CCND1 have been reported to be recurrently mutated in MCL, but do not fully explain the biology and do not adequately account for the wide spectrum of clinical manifestations, response to treatment and prognosis. The aim of this study was to discover new somatic mutations that could contribute to our understanding of the pathogenesis of MCL. Methods: In our discovery cohort, we sequenced the transcriptomes of 18 clinical samples (11 diagnostic and 7 progression biopsies) and 2 mantle cell lymphoma-derived cell lines (Mino and Jeko-1). For this purpose, whole transcriptome shotgun sequencing was performed on RNA extracted from fresh frozen tissue. We assembled an extension cohort of 103 diagnostic patient samples and 4 additional cell lines (Rec-1, Z-138, Maver-1, JVM-2), and performed Sanger sequencing of NOTCH1 exons 26, 27 and 34 on genomic DNA. We further exposed the 6 cell lines to 1 μM of the γ-secretase inhibitor XXI (compound E) for 7 days and measured cellular proliferation with an EdU incorporation assay. Survival analysis was carried out in the 113 patients with diagnostic biopsies and available outcome data. Results: NOTCH1 mutations were found in 14 out of 121 patient samples (11.6%) and in 2 out of 6 cell lines, Mino and Rec-1 (33.3%). The majority of these mutations (12 out of 14) lie in exon 34 that encodes the PEST domain of NOTCH1 and consist of either small frameshift-causing indels (10 cases) or nonsense mutations (2 cases). These mutations are predicted to cause truncations of the C-terminal PEST domain. To gain further insight into functional relevance, we treated 6 cell lines with compound E, an inhibitor of the γ-secretase complex that plays a critical role in the release of the intracellular domain of NOTCH1 after ligand-induced activation. In Rec-1, that harbours a NOTCH1 mutation, we observed a significant decrease in proliferation (mean percentage of cells in culture incorporating EdU decreasing from 47.5% to 1.4%, p<.001). No effect of compound E was observed in Mino, the other cell line with a NOTCH1 mutation, nor in the 4 cell lines that are wild type for NOTCH1. Outcome correlation analysis showed that NOTCH1 mutations are associated with poor overall survival (1.56 versus 3.86 years respectively, p=.001), but not with significantly shortened progression-free survival (0.88 versus 1.73 years respectively, p=.07). Discussion: We have identified recurrent mutations in NOTCH1 in a subset of patients with MCL (11.6%). The frequency and the pattern of mutations are strikingly similar to what has recently been reported in chronic lymphocytic leukemia, the other major CD5 positive B-cell malignancy (Nature, 2011 Jun 5, 475:101–105 and J Exp Med, 2011 Jul 4, 208:1389–1401). NOTCH1 mutations are associated with adverse prognosis as evidenced by shortened overall survival. This latter finding, however, should ideally be validated in a larger and uniformly treated cohort. Finally, the sensitivity of the Rec-1 cell line to compound E suggests that NOTCH1 mutations could serve as the target for tailored therapy in mantle cell lymphoma. Disclosures: Sehn: Roche/Genentech: Consultancy, Honoraria, Research Funding. Connors:Roche: Research Funding.

Combination Of Ibrutinib With ABT-199, a BCL-2 Pathway Inhibitor: Effective Therapeutic Strategy In a Novel Mantle Cell Lymphoma Cell Line Model

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 645-645 ◽  
Author(s):  
Xiaoxian Zhao ◽  
Juraj Bodo ◽  
Danyu Sun ◽  
Jeffrey J. Lin ◽  
Lisa Durkin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Therapeutic Strategy ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Down Regulation ◽  
Mantle Cell ◽  
Bcr Signaling ◽  
Nsg Mouse

Abstract Background Mantle cell lymphoma (MCL) is an aggressive subtype of Non-Hodgkin Lymphoma associated with poor prognosis. Constitutive activation of B-cell receptor (BCR) signaling plays an essential role for the survival and proliferation of malignant B-cells. Targeting Bruton’s tyrosine kinase (BTK), a component of BCR signaling pathway, with ibrutinib is a promising strategy. As a single agent, complete and partial response rates of 21% and 47%, respectively, were observed in a phase 2 study for relapsed or refractory MCL. Simultaneous inhibition of multiple biologic pathways has the potential to result in a synergism. We combined ibrutinib with ABT-199, a BH3 mimetic that selectively targets the BCL-2 pathway, and tested their in vitroefficacy against MCL. Experimental design A novel MCL cell line, CCMCL1, and four other MCL cell lines (Jeko-1, Mino, JVM2, Rec-1) were used for flow cytometry-based apoptosis and cell cycle analyses to evaluate the combinational effect of ibrutinib with ABT-199 (ChemieTek. Indianpolis. IN). The interaction between drugs was examined with Calcusyn software and combination index values served to determine the combined effect as synergistic (<1), additive (=1), or antagonistic (>1). Immunoblotting was performed to investigate signaling pathways of MCL cells exposed to these agents. Results CCMCL1 was derived from primary leukemic MCL cells. Cells were initially directly injected via tail vein into an NSG mouse. Engrafted cells were then isolated at 10 weeks from spleen and placed into routine cell culture. Immunophenotyping showed CCMCL1 cells have similar characteristics as the primary patient MCL cells, which expressed CD5, CD19, CD20, FMC7 and monotypic kappa light chain. Immunohistochemical staining of engrafted mouse spleen tissue showed expression of cyclin D1 and SOX11. The karyotype is highly complex with an IGH@/CCND1 fusion by metaphase FISH. In addition to spleen, MCL cell infiltration was observed in mouse liver, bone marrow, blood, brain, lung, kidney and intestine. In vitro cultured CCMCL1 cells underwent apoptosis upon expose to ibrutinib and ABT-199 as single agents. Combination of these two drugs resulted in synergistic induction of apoptosis (Table 1). Synergism was also observed with Jeko-1, Mino, JVM-2 and Rec-1 cells. Immunoblotting showed CCMCL1 cells have constitutive expression of cyclin D1, SOX11, PAX5 and MCL1. Ibrutinib as a single agent induced a rapid down-regulation of SOX11 and MCL1, while combination of ibrutinib with ABT-199 further enhanced down regulation of SOX11, followed by down-regulation of PAX5 at a later time point. We are currently testing the in vivo efficacy of combining these two drugs in a CCMCL1 NSG mouse model. Conclusion Our CCMCL1/NSG mouse model is a new model for pre-clinical assessment of MCL treatment approaches. Combination of ibrutinib with ABT-199 has synergistic effect of apoptotic induction in CCMCL1 as well as four other MCL cell lines tested. Ibrutinib or ibruitnib/ABT-199 combination induced apoptosis of MCL is associated with down-regulation of SOX11 and PAX5. Simultaneous down regulation of MCL1 via ibrutinib and targeting of BCL2 may contribute to the in vitrosynergism observed. These data support further investigation of this novel therapeutic strategy. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document