56 results on '"Janz, Siegfried"'
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2. Waldenström Macroglobulinemia: Clinical and Immunological Aspects, Natural History, Cell of Origin, and Emerging Mouse Models.
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Janz, Siegfried
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LYMPHOPROLIFERATIVE disorders , *ACADEMIC medical centers , *ANIMAL experimentation , *B cell lymphoma , *CELL physiology , *HEMATOLOGY , *IMMUNITY , *IMMUNOGLOBULINS , *EVALUATION of medical care , *MICE , *DIAGNOSIS - Abstract
Waldenström macroglobulinemia (WM) is a rare and currently incurable neoplasm of IgM-expressing B-lymphocytes that is characterized by the occurrence of amonoclonal IgM (mIgM) paraprotein in blood serum and the infiltration of the hematopoietic bone marrow with malignant lymphoplasmacytic cells.The symptoms of patients with WM can be attributed to the extent and tissue sites of tumor cell infiltration and the magnitude and immunological specificity of the paraprotein .WM presents fascinating clues on neoplastic B-cell development, including the recent discovery of a specific gain-of-function mutation in the MYD88 adapter protein. This not only provides an intriguing link to new findings that natural effector IgM+IgD+ memory B-cells are dependent on MYD88 signaling, but also supports the hypothesis that WM derives from primitive, innate-like B-cells, such as marginal zone and B1 B-cells. Following a brief review of the clinical aspects and natural history of WM, this review discusses the thorny issue of WM's cell of origin in greater depth. Also included are emerging, genetically engineered mouse models of human WM that may enhance our understanding of the biologic and genetic underpinnings of the disease and facilitate the design and testing of new approaches to treat and prevent WM more effectively. [ABSTRACT FROM AUTHOR]
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- 2013
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3. Performance Optimization of a Reconfigurable Waveguide Digital Optical Switch on InGaAsP—InP: Design, Material, and Carrier Dynamics.
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Ng, Sandy, Janz, Siegfried, McKinnon, W. Ross, Barrios, Pedro, Delage, André, and Syrett, Barry A.
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ALLOYS , *WAVEGUIDES , *SWITCHING systems (Telecommunication) , *OPTICAL switching , *ELECTRONIC industries , *DEVICES (Heraldry) , *ELECTRIC power distribution , *SWITCHING theory , *INDUSTRIAL productivity - Abstract
The design and performance of an InGaAsP-InP 1 x 2 reconfigurable waveguide digital optical switch (RW-DOS) actuated by carrier-induced refractive index modulation is de- scribed. Using a device model based on the two-dimensional beam propagation method, we present an analysis of the role of material bandgap, carrier lifetime, and waveguide design on the switch performance. The model results are compared with experimental measurements of carrier-induced index change and switching performance for RW-DOS devices and test structures fabricated in InGaAsP alloys with waveguide core compositions of Q = 1.2, Q = 1.3, and Q = 1.4 μm. We discuss compromises between power consumption, switching speed, and propagation loss. The optimized InGaAsP-InP devices exhibited better than 25-dB switching contrast ratio and require less than 20-mA drive current. [ABSTRACT FROM AUTHOR]
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- 2007
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4. Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF.
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Fujita, Ken-ichi and Janz, Siegfried
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CANCER , *BONE cells , *PRECANCEROUS conditions , *ALKALINE phosphatase , *PROTEINS - Abstract
Background: Enhanced osteoblast-dependent osteoclastogenesis due to inhibition of Wnt/β-catenin signaling in bone morphogenic protein (BMP)-driven osteoprogenitors has been repeatedly implicated in the natural history of cancer-associated osteolytic lesions, but the mechanism of this bone loss is poorly understood. Methods: We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation. Results: We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/β-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-κB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D3 and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective. Conclusion: Our results suggest that inhibited Wnt/β-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss. [ABSTRACT FROM AUTHOR]
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- 2007
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5. Myc translocations in B cell and plasma cell neoplasms
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Janz, Siegfried
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B cells , *IMMUNOGLOBULINS , *PLASMA cells , *CANCER , *BIOCHEMICAL genetics - Abstract
Abstract: Chromosomal translocations that join the cellular oncogene Myc (c-myc) with immunoglobulin (Ig) heavy-chain (Igh) or light-chain (Igk, Igl) loci are widely believed to be the crucial initiating oncogenic events in the development of B cell and plasma cell neoplasms in three mammalian species: Burkitt lymphoma (BL) in human beings, plasmacytoma (PCT) in mice, and immunocytoma in rats. Among the Myc–Ig translocations found in these neoplasms, mouse PCT T(12;15)(Igh–Myc) is of special interest because it affords a uniquely useful model system to study the fundamental outstanding questions on the mechanisms, genetics, and biological consequences of Myc translocations. Mouse T(12;15) is the direct counterpart of the human BL t(8;14)(q24;q32) translocation and thus of great relevance for human cancer. Mouse T(12;15) is the only cancer-associated translocation in mice that occurs with high incidence, spontaneity, and cell-type specificity. Due to the development of PCR methods for the detection of the underlying reciprocal Myc–Igh junction fragments, it is now known that mouse T(12;15) can be a dynamic process that begins with the genetic exchange of Myc and the Igh switch μ region (Sμ), progresses by class switch recombination (CSR) just 3′ of the translocation break site, and then undergoes further clonal diversification by micro-deletions in the junction flanks. The molecular pathway that subverts CSR to mediate trans-chromosomal joining of Myc and Sμ (translocation origin) and secondary modification of Myc–Igh junctions (translocation “remodeling”) has not been elucidated, but recent evidence indicates that it includes CSR factors, such as the activation-induced cytidine deaminase (AID), that may also be involved in the ongoing neoplastic progression of the translocation-bearing tumor precursor. Transgenic mouse models of T(12;15)/t(8;14), including newly developed “iMyc” gene-insertion mice, will be useful in elucidating the role of these CSR factors in the progression of Myc-induced B cell tumors. [Copyright &y& Elsevier]
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- 2006
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6. Uncovering MYC's full oncogenic potential in the hematopoietic system.
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Janz, Siegfried
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ONCOGENES , *CANCER genetics , *HEMATOPOIETIC system , *BLOOD cells , *LYMPHOMAS - Abstract
MYC is an important oncogene in hematopoietic neoplasms in humans, yet the mechanism by which MYC induces the malignant transformation of blood cells has remained elusive. Postulating that mouse models of deregulated MYC expression may be helpful for advancing our understanding of MYC-induced hematopoietic malignancies, Suzanne Cory and her associates took advantage of the Vav promoter to express MYC throughout the hematopoietic system in transgenic mice. In this issue of Oncogene, they report (Smith et al.) that the newly developed strain, referred to as VavP-MYC17, is prone to mature T-cell lymphomas (for which few good mouse models exist). They further show that VavP-MYC17 mice that are devoid of mature T cells (and B cells) because of genetic deficiency in Rag1 recombinase develop neoplasms of three distinct blood cell lineages: pre-T cells, pro-B cells, and macrophages. These findings establish that VavP-driven MYC has broad oncogenic potential in the hematopoietic compartment and prompts new views of the cellular assaults of deregulated MYC on hematopoietic stem and early progenitor cells.Oncogene (2005) 24, 3541-3543. doi:10.1038/sj.onc.1208473 Published online 21 March 2005 [ABSTRACT FROM AUTHOR]
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- 2005
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7. Chimeric antigen receptor and bispecific T‐cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.
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Hammons, Lindsay, Haider, Shabi, Portuguese, Andrew J., Banerjee, Rahul, Szabo, Aniko, Pasquini, Marcelo, Chhabra, Saurabh, Radhakrishnan, Sabarinath, Mohan, Meera, Narra, Ravi, Dong, Jing, Janz, Siegfried, Shah, Nirav N., Hamadani, Mehdi, D'Souza, Anita, Hari, Parameswaran, and Dhakal, Binod
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CHIMERIC antigen receptors , *MULTIPLE myeloma , *CYTOKINE release syndrome , *T cells , *ANTIGEN receptors , *GRAFT versus host disease , *DISEASE exacerbation - Abstract
Summary: Chimeric antigen receptor T‐cell (CAR‐T) therapy and bispecific T‐cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR‐T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo‐HCT). Thirty‐three MM patients with prior allo‐HCT received CAR‐T (n = 24) or BsAb (n = 9) therapy. CAR‐T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR‐T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR‐T and 78% of BsAb recipients, while immune effector cell‐associated neurotoxicity syndrome (ICANS) was observed in three CAR‐T patients. Infections of grade ≥3 were reported in 50% of CAR‐T and 44% of BsAb recipients. No exacerbation of graft‐versus‐host disease occurred except in one BsAb recipient. CAR‐T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo‐HCT. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Practical ring-resonator thermometer with an uncertainty of 10 mK.
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Dedyulin, Sergey, Grzetic-Muffo, Alexander, Janz, Siegfried, Xu, Dan-Xia, Wang, Shurui, Vachon, Martin, and Weber, John
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THERMOMETERS , *OPTICAL polarization , *TEMPERATURE sensors , *METROLOGY - Abstract
Silicon ring resonators are currently being assessed by several national metrology organizations as thermometers for use in calibration laboratories and in high-accuracy commercial applications. In this paper, we report the improvements to our first prototype of Si ring-resonator thermometer including narrower ring resonances, different light polarization in the ring and smaller-footprint probe housing. We evaluated the second prototype in the stirred liquid bath between 23 °C and 80 °C over the span of 11 months and we present, for the first time, the full uncertainty budget for the packaged ring-resonator thermometer. The combined 10-mK standard uncertainty for our ring-resonator thermometer is not only identical to the repeatability reported previously for an unpackaged ring resonator but it also includes an 11-month long-term stability component. This result heralds a commercial ring-resonator thermometer. • The experimental results with the second (improved) ring-resonator thermometer prototype are described. • Full uncertainty budget for the packaged ring-resonator thermometer is presented for the first time. • The combined standard uncertainty of 9.2 mK is identical to repeatability of unpackaged thermometer from the literature. • 11-month long-term stability of ring-resonator thermometer is evaluated for the first time. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Mouse model of MYD88L265P-dependent DLBCL.
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Janz, Siegfried
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B cells , *LABORATORY mice , *ANIMAL models in research , *GENETICS , *TOLL-like receptors , *INTERLEUKIN-1 - Abstract
The author focuses on the study by G. Knittel and colleagues regarding the expression of the mutant MYD88 L265 in rodent's B lymphocytes. Topics discussed include the use of genetically engineered mouse model (GEMM) for the examination of the role played by MYD88 L265 in the diffuse large B-cell lymphoma (DLBCL's) genetics and biology, the connection between Toll-like receptor and interleukin-1 receptor,and the expression of B-cell leukemia.
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- 2016
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10. A gene signature can predict risk of MGUS progressing to multiple myeloma.
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Sun, Fumou, Cheng, Yan, Ying, Jun, Mery, David, Al Hadidi, Samer, Wanchai, Visanu, Siegel, Eric R., Xu, Hongwei, Gai, Dongzheng, Ashby, Timothy Cody, Bailey, Clyde, Chen, Jin-Ran, Schinke, Carolina, Thanendrarajan, Sharmilan, Zangari, Maurizio, Janz, Siegfried, Barlogie, Bart, Van Rhee, Frits, Tricot, Guido, and Shaughnessy Jr, John D.
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MULTIPLE myeloma , *IMMUNOGLOBULIN light chains , *GENE expression profiling , *BIOMARKERS , *GENOMICS - Abstract
Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Serum markers are currently used to stratify MGUS patients into clinical risk groups. A molecular signature predicting MGUS progression has not been produced. We have explored the use of gene expression profiling to risk-stratify MGUS and developed an optimized signature based on large samples with long-term follow-up. Microarrays of plasma cell mRNA from 334 MGUS with stable disease and 40 MGUS that progressed to MM within 10 years, was used to define a molecular signature of MGUS risk. After a three-fold cross-validation analysis, the top thirty-six genes that appeared in each validation and maximized the concordance between risk score and MGUS progression were included in the gene signature (GS36). The GS36 accurately predicted MGUS progression (C-statistic is 0.928). An optimal cut-point for risk of progression by the GS36 score was found to be 0.7, which identified a subset of 61 patients with a 10-year progression probability of 54.1%. The remainder of the 313 patients had a probability of progression of only 2.2%. The sensitivity and specificity were 82.5% and 91.6%. Furthermore, combination of GS36, free light chain ratio and immunoparesis identified a subset of MGUS patients with 82.4% risk of progression to MM within 10 years. A gene expression signature combined with serum markers created a highly robust model for predicting risk of MGUS progression. These findings strongly support the inclusion of genomic analysis in the management of MGUS to identify patients who may benefit from more frequent monitoring. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Clonality in Kaposi's Sarcoma.
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Rabkin, Charles S., Janz, Siegfried, and Zhuang, Zhengping
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LETTERS to the editor , *KAPOSI'S sarcoma - Abstract
A response is presented by Charles S. Rabkin, Siegfried Janz and Zhengping Zhuang to a letter to the editor about their article "Monoclonal origin of multicentric Kaposi's sarcoma lesions" which appeared in the April 3, 1997 issue.
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- 1997
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12. Monoclonal Origin of Multicentric Kaposi's Sarcoma Lesions.
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Rabkin, Charles S., Janz, Siegfried, Lash, Alex, Coleman, Allen E., Musaba, Elizabeth, Liotta, Lance, Biggar, Robert J., and Zhuang, Zhengping
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KAPOSI'S sarcoma - Abstract
Background: Kaposi's sarcoma has features of both hyperplastic proliferation and neoplastic growth. Multiple lesions, in which spindle cells are prominent, often arise synchronously over widely dispersed areas. We tested the hypothesis that the spindle cells in these multicentric lesions originate from a single clone of precursor cells. Methods: To determine whether Kaposi's sarcoma is a monoclonal disorder, we assessed the methylation patterns of the androgen-receptor gene (HUMARA) in multiple lesions from women with the acquired immunodeficiency syndrome. In polyclonal tissues, about half the copies of each HUMARA allele are methylated, whereas in cells derived from a single clone all the copies of only one allele are methylated. To minimize contamination by normal DNA, we used microdissection to isolate areas composed primarily of spindle cells, the putative tumor cells. Results: Eight patients with a total of 32 tumors were studied. Of these tumors, 28 had highly unbalanced methylation patterns (i.e., predominant methylation of one HUMARA allele). In all the tumors that had unbalanced methylation from a given patient, the same allele predominated. Conclusions: These data indicate that Kaposi's sarcoma is a disseminated monoclonal cancer and that the changes that permit the clonal outgrowth of spindle cells occur before the disease spreads. (N Engl J Med 1997;336:988-93.) [ABSTRACT FROM AUTHOR]
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- 1997
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13. WDR26 and MTF2 are therapeutic targets in multiple myeloma.
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Sun, Fumou, Cheng, Yan, Riordan, Jesse D., Dupuy, Adam, Dubois, Wendy, Pisano, Michael, Dong, Jing, Mock, Beverly, Zhan, Fenghuang, Hari, Parameswaran, and Janz, Siegfried
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DRUG target , *MULTIPLE myeloma , *MOUSE leukemia viruses , *GENETIC testing , *DNA sequencing , *TUMOR suppressor genes - Abstract
Unbiased genetic forward screening using retroviral insertional mutagenesis in a genetically engineered mouse model of human multiple myeloma may further our understanding of the genetic pathways that govern neoplastic plasma cell development. To evaluate this hypothesis, we performed a tumor induction study in MYC-transgenic mice infected as neonates with the Moloney-derived murine leukemia virus, MOL4070LTR. Next-generation DNA sequencing of proviral genomic integration sites yielded rank-ordered candidate tumor progression genes that accelerated plasma cell neoplasia in mice. Rigorous clinical and biological validation of these genes led to the discovery of two novel myeloma genes: WDR26 (WD repeat-containing protein 26) and MTF2 (metal response element binding transcription factor 2). WDR26, a core component of the carboxy-terminal to LisH (CTLH) complex, is overexpressed or mutated in solid cancers. MTF2, an ancillary subunit of the polycomb repressive complex 2 (PRC2), is a close functional relative of PHD finger protein 19 (PHF19) which is currently emerging as an important driver of myeloma. These findings underline the utility of genetic forward screens in mice for uncovering novel blood cancer genes and suggest that WDR26-CTLH and MTF2-PRC2 are promising molecular targets for new approaches to myeloma treatment and prevention. [ABSTRACT FROM AUTHOR]
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- 2021
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14. Distribution of t(14;18)-positive, putative lymphoma precursor cells among B-cell subsets in healthy individuals.
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Hirt, Carsten, Dölken, Gottfried, Janz, Siegfried, and Rabkin, Charles S.
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B cells , *LYMPHOMAS , *POLYMERASE chain reaction , *IMMUNOPHENOTYPING , *LYMPHOCYTES , *IMMUNOGLOBULINS - Abstract
The t(14;18)(q32;q21) is the characteristic chromosomal translocation of follicular lymphoma (FL). Highly sensitive polymerase chain reaction (PCR) techniques can also detect t(14;18)-sequences in the blood and lymphoid tissues of healthy individuals (HI). The aim of this study was to determine the immunophenotypic markers of t(14;18)-positive cells in HI and to relate these features to lymphocyte maturation. B cells from 10 subjects with t(14;18)-positive and three subjects with t(14;18)-negative peripheral blood mononuclear cells (PBMC) were fluorescence-activated cell sorted for antigen-naïve (CD27−), immunoglobulin M (IgM) memory (IgM+CD27+) and switched memory (IgM− CD27+) cells. t(14;18)-recombinations were detected by quantitative PCR. Among PBMC-positive subjects, t(14;18)-frequency was significantly higher in IgM memory (median: 380/106) than in antigen-naïve (median: 16/106) or switched memory (median: 5/106) B cells. All PBMC-negative subjects nevertheless had detectable t(14;18) in sorted B cells; levels were lower than in PBMC-positive subjects, but had the same relative predominance. These results suggest that t(14;18) is generated during early B-cell development in the bone marrow and that affected cells may mature and expand in germinal centres. t(14;18)-frequency was highest in IgM memory cells, a B-cell subset that shares immunophenotypic similarities with FL. The significance of these cells as lymphoma precursors or indicators of lymphoma risk remains to be established. [ABSTRACT FROM AUTHOR]
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- 2007
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15. Elevated presence of retrotransposons at sites of DNA double strand break repair in mouse models of metabolic oxidative stress and MYC-induced lymphoma
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Rockwood, Lynne D., Felix, Klaus, and Janz, Siegfried
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The chromosomally integrated shuttle vector pUR288 contains a lacZ reporter gene to study mutagenesis in vivo. We used pUR288 to compare patterns of genomic instability in two mouse models, lymphoma resulting from deregulated c-MYC expression (λ-MYC), and endogenous oxidative stress caused by partial glucose 6-phosphate dehydrogenase (G6PD) deficiency. We found previously that spontaneous mutations in both models were predominantly genomic rearrangements of lacZ with mouse sequences, while most mutations in controls were point mutations. Here, we characterized the fine structure of 68 lacZ/mouse rearrangements from λ-MYC lymphomas and G6PD deficient mice by sequencing breakpoint junctions and determining the origin of recombining mouse sequences. Fifty-eight of 68 (85%) recombination partners were identified. The structure of rearrangements from both λ-MYC and G6PD deficient mice were remarkably alike. Intra-chromosomal deletions and inversions were common, occurring in 41% (24/58) of rearrangements, while 59% (34/58) were random translocations between lacZ and other chromosomes. Signatures of double strand break repair by nonhomologous end joining were observed at breakpoint junctions; 37% (25/68) contained 1–4 bp microhomologies, while the remaining breakpoints had no sequence homology. Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons, which constitute ∼10% of the mouse genome, were present at 25% (17/68) of breakpoints, suggesting their participation in rearrangements. The similarity in the structure of rearrangements is consistent with the hypothesis that genetic rearrangements in λ-MYC lymphomas and G6PD deficient mice result from the same mechanism, mutagenic repair of DNA double strand breaks arising from oxidative damage. [Copyright &y& Elsevier]
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- 2004
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16. Paradoxical decrease in mutant frequencies and chromosomal rearrangements in a transgenic lacZ reporter gene in Ku80 null mice deficient in DNA double strand break repair
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Rockwood, Lynne D., Nussenzweig, André, and Janz, Siegfried
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DNA repair , *MUTAGENESIS , *GENOMICS - Abstract
Repair of DNA double strand breaks (DSB), either by homologous recombination (HR) or nonhomologous end-joining (NHEJ), is essential to maintain genomic stability. To examine the impact of NHEJ deficiency on genomic integrity in Ku80 null (Ku−) mice, the chromosomally integrated shuttle vector pUR288, which includes a lacZ reporter gene, was used to measure mutations in vivo. Unexpectedly, a significant decrease was found in mutant frequencies of Ku− liver (
5.04×10−5 ) and brain (4.55×10−5 ) compared to tissues obtained from normal (Ku+) littermates (7.92×10−5 and7.30×10−5 , respectively). No significant difference was found in mutant frequencies in spleen from Ku− (7.21×10−5 ) and Ku+ mice (8.16×10−5 ). The determination of the mutant spectrum in lacZ revealed the almost complete absence of chromosomal rearrangements (R) in Ku− tissues (0.5%, 3/616), a notable distinction from Ku+ controls (16.7%, 104/621). These findings suggest that accurate repair of DSB by HR and elimination of cells with unrepaired DNA damage by apoptosis are capable of maintaining genomic stability of the lacZ reporter in Ku− mice. [Copyright &y& Elsevier]- Published
- 2003
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17. Eu/Su transposition into Myc is sometimes a precursor for T(12;15) translocation in mouse B cells.
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Kovalchuk, Alexander L, Kim, Joong Su, and Janz, Siegfried
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IMMUNOGLOBULINS , *MYC oncogenes , *LYMPH nodes , *TUMORS - Abstract
Misguided immunoglobulin (Ig) class switch recombination (CSR) has been implicated in the origin of Myc-activating chromosomal translocations, T(12;15), in BALB/c mouse plasmacytomas (PCTs). CSR has also been involved in the progression of T(12;15); for example, the approximation of Myc to the 3'-Ca enhancer. This study provides evidence for an additional mechanism by which aberrant CSR may facilitate T(12;15): transposition of Ig heavy-chain (IgH) sequences to Myc. Five IgH transposons containing the intronic heavy-chain enhancer, Eu, and a truncated switch u region, Su, were found in the first intron of Myc in lymph node cells of IL-6 transgenic BALB/c mice. In two cases Eu/Sutransposition primed Myc to get involved in apparent trans-chromosomal CSR to C?1, presumably leading to T(12;15). Translocations preceded by Eu/Sutransposition can sometimes be distinguished from de novo translocations by molecular fingerprints in translocation breakpoint regions (Ig switch region [S] inversions and unusual gene orders in composite S regions). The presence of such fingerprints in some PCTs suggests that the tumors sometimes evolve from transposition-bearing precursors. We propose that Eu/Sutransposition to Myc may facilitate plasmacytomagenesis by sensitizing Myc to undergo T(12;15) translocation. T(12;15), in turn, juxtaposes Myc to the 3'-Ca enhancer, which appears to be required for deregulating Myc in a manner that is conducive to PCT development.Oncogene (2003) 22, 2842-2850. doi:10.1038/sj.onc.1206345 [ABSTRACT FROM AUTHOR]
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- 2003
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18. TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies.
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Can Li, Jiliang Xia, Franqui-Machin, Reinaldo, Fangping Chen, Yanjuan He, Ashby, Timothy Cody, Feixiang Teng, Hongwei Xu, Dingxiao Liu, Dongzheng Gai, Johnson, Sarah K., van Rhee, Frits, Janz, Siegfried, Shaughnessy Jr., John D., Tricot, Guido, Frech, Ivana, Fenghuang Zhan, Li, Can, Xia, Jiliang, and Chen, Fangping
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B cell lymphoma , *ONCOGENIC proteins , *CANCER invasiveness , *MULTIPLE myeloma , *DRUG target , *BORTEZOMIB - Abstract
Multiple myeloma (MM), a terminally differentiated B cell malignancy, remains difficult to cure. Understanding the molecular mechanisms underlying the progression of MM may identify therapeutic targets and lead to a fundamental shift in treatment of the disease. Deubiquitination, like ubiquitination, is a highly regulated process, implicated in almost every cellular process. Multiple deubiquitinating enzymes (DUBs) have been identified, but their regulation is poorly defined. Here, we determined that TRIP13 increases cellular deubiquitination. Overexpression of TRIP13 in mice and cultured cells resulted in excess cellular deubiquitination by enhancing the association of the DUB USP7 with its substrates. We show that TRIP13 is an oncogenic protein because it accelerates B cell tumor development in transgenic mice. TRIP13-induced resistance to proteasome inhibition can be overcome by a USP7 inhibitor in vitro and in vivo. These findings suggest that TRIP13 expression plays a critical role in B cell lymphoma and MM by regulating deubiquitination of critical oncogenic (NEK2) and tumor suppressor (PTEN, p53) proteins. High TRIP13 identifies a high-risk patient group amenable to adjuvant anti-USP7 therapy. [ABSTRACT FROM AUTHOR]
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- 2021
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19. CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma.
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Gu, Chunyan, Wang, Wang, Tang, Xiaozhu, Xu, Tingting, Zhang, Yanxin, Guo, Mengjie, Wei, Rongfang, Wang, Yajun, Jurczyszyn, Artur, Janz, Siegfried, Beksac, Meral, Zhan, Fenghuang, Seckinger, Anja, Hose, Dirk, Pan, Jingxuan, and Yang, Ye
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MULTIPLE myeloma , *OSTEOCLASTS , *BONE growth , *BONE marrow cells , *B cells , *ACID phosphatase , *CELL proliferation , *CIRCULAR RNA , *CHECKPOINT kinase 1 - Abstract
Background: Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. Methods: Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. Results: We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. Conclusions: Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche. [ABSTRACT FROM AUTHOR]
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- 2021
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20. HNRNPA2B1 promotes multiple myeloma progression by increasing AKT3 expression via m6A-dependent stabilization of ILF3 mRNA.
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Jiang, Fengjie, Tang, Xiaozhu, Tang, Chao, Hua, Zhen, Ke, Mengying, Wang, Chen, Zhao, Jiamin, Gao, Shengyao, Jurczyszyn, Artur, Janz, Siegfried, Beksac, Meral, Zhan, Fenghuang, Gu, Chunyan, and Yang, Ye
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MULTIPLE myeloma , *RNA metabolism , *MESSENGER RNA , *CELL proliferation , *TUMOR growth , *CD38 antigen - Abstract
N6-methyladenosine (m6A) modification is the most prevalent modification in eukaryotic RNAs while accumulating studies suggest that m6A aberrant expression plays an important role in cancer. HNRNPA2B1 is a m6A reader which binds to nascent RNA and thus affects a perplexing array of RNA metabolism exquisitely. Despite unveiled facets that HNRNPA2B1 is deregulated in several tumors and facilitates tumor growth, a clear role of HNRNPA2B1 in multiple myeloma (MM) remains elusive. Herein, we analyzed the function and the regulatory mechanism of HNRNPA2B1 in MM. We found that HNRNPA2B1 was elevated in MM patients and negatively correlated with favorable prognosis. The depletion of HNRNPA2B1 in MM cells inhibited cell proliferation and induced apoptosis. On the contrary, the overexpression of HNRNPA2B1 promoted cell proliferation in vitro and in vivo. Mechanistic studies revealed that HNRNPA2B1 recognized the m6A sites of ILF3 and enhanced the stability of ILF3 mRNA transcripts, while AKT3 downregulation by siRNA abrogated the cellular proliferation induced by HNRNPA2B1 overexpression. Additionally, the expression of HNRNPA2B1, ILF3 and AKT3 was positively associated with each other in MM tissues tested by immunohistochemistry. In summary, our study highlights that HNRNPA2B1 potentially acts as a therapeutic target of MM through regulating AKT3 expression mediated by ILF3-dependent pattern. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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21. Deletional remodeling of c-myc-deregulating chromosomal translocations.
- Author
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Kovalchuk, Alexander L, Müller, Jürgen R, and Janz, Siegfried
- Subjects
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CHROMOSOMAL translocation , *MYC oncogenes , *IMMUNOGLOBULIN genes - Abstract
Evidence is presented for the existence of a novel remodeling-by-deletion mechanism that alters the fine structure of c-myc-deregulating chromosomal translocations in t(12;15)-positive BALB/c plasmacytomas. DNA sequence analysis of the t(12;15) in five primary tumors revealed the co-existence of precursor cells harboring genetic recombinations between the immunoglobulin heavy-chain μ locus (Ighμ) and c-myc with clonally related progenitors containing rearrangements between the immunoglobulin heavy-chain α locus (Ighα) and c-myc. Clonal relatedness was based upon unique junction fragments between the switch region of Ighμ and c-myc. Sμ/c-myc junctions are thus useful clonotypic markers for monitoring the conversion of Ighμ/c-myc-positive tumor precursor clones into Ighα/c-myc-positive plasmacytomas. Aberrant isotype switch recombination appears to be the most likely mechanism effecting this conversion event (other possibilities are discussed) which may help to explain the preferred usage of the Ighα locus in recombinations with c-myc in t(12;15)-positive plasma cell tumors in BALB/c mice. [ABSTRACT FROM AUTHOR]
- Published
- 1997
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22. Association of adverse events and associated cost with efficacy for approved relapsed and/or refractory multiple myeloma regimens: A Bayesian network meta-analysis of phase 3 randomized controlled trials.
- Author
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Dhakal, Binod, Narra, Ravi K., Giri, Smith, Szabo, Aniko, Smunt, Timothy L., Ghose, Sanjoy, Pathak, Lakshmi Kant, Aryal, Madan, Hamadani, Mehdi, Chhabra, Saurabh, Janz, Siegfried, D'Souza, Anita, and Hari, Parameswaran N.
- Subjects
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MULTIPLE myeloma , *ADVERSE health care events , *META-analysis , *PROGRESSION-free survival , *COST , *THERAPEUTIC use of antineoplastic agents , *RESEARCH , *CLINICAL trials , *THALIDOMIDE , *OLIGOPEPTIDES , *DEXAMETHASONE , *RESEARCH methodology , *ANTINEOPLASTIC agents , *MEDICAL care costs , *MEDICAL cooperation , *EVALUATION research , *TREATMENT effectiveness , *COMPARATIVE studies , *RESEARCH funding , *PROBABILITY theory - Abstract
Background: Several new treatment options have been approved for relapsed and/or refractory multiple myeloma (RRMM). In this systematic review, associations of the efficacy of each approved regimen with adverse events (AEs) and the total cost per cycle were compared with a Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs).Methods: Scopus, Cochrane, PubMed Publisher, and Web of Science were searched from January 1999 to July 2018 for phase 3 RCTs of regimens (approved by the US Food and Drug Administration) used in RRMM. The relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities. The primary efficacy, safety, and cost outcomes were progression-free survival with the regimen, grade 3 to 4 AEs, and the total cost per cycle (regimen cost plus average cost of managing AEs).Results: Fifteen studies including 7718 patients and evaluating 14 different regimens were identified. Daratumumab, lenalidomide, and dexamethasone were ranked highest for reducing progression (hazard ratio, 0.13; 95% credible interval, 0.09-0.19; SUCRA, 1) but carried the highest probability of total cost per cycle ($41,420; 95% Credible Interval [CrCl], $58,665-$78,041; SUCRA, 0.02). Panobinostat, bortezomib, and dexamethasone were the least effective and least safe (SUCRA, 0.24), whereas bortezomib, thalidomide, and dexamethasone emerged as least effective with the highest total cost per cycle (SUCRA, 0.33). Carfilzomib and dexamethasone emerged as the winner when this regimen was considered in terms of efficacy and safety (SUCRA, 0.61) and efficacy and total cost per cycle (SUCRA, 0.60).Conclusions: The results of this NMA can provide additional guidance for the decision-making process when one is choosing the most appropriate regimen for RRMM. [ABSTRACT FROM AUTHOR]- Published
- 2020
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23. Identification and Characterization of Tumor-Initiating Cells in Multiple Myeloma.
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Gao, Minjie, Bai, Hua, Jethava, Yogesh, Wu, Yujie, Zhu, Yuqi, Yang, Ye, Xia, Jiliang, Cao, Huojun, Franqui-Machin, Reinaldo, Nadiminti, Kalyan, Thomas, Gregory S, Salama, Mohamed E, Altevogt, Peter, Bishop, Gail, Tomasson, Michael, Janz, Siegfried, Shi, Jumei, Chen, Lijuan, Frech, Ivana, and Tricot, Guido
- Subjects
- *
REVERSE transcriptase polymerase chain reaction , *MULTIPLE myeloma , *INDUCED pluripotent stem cells , *FLUORESCENT antibody technique , *RESEARCH , *XENOGRAFTS , *ANIMAL experimentation , *CARCINOGENESIS , *RESEARCH methodology , *EVALUATION research , *MEDICAL cooperation , *COMPARATIVE studies , *STEM cells , *RESEARCH funding , *MICE , *DRUG resistance in cancer cells - Abstract
Background: Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant.Methods: Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group.Results: CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo.Conclusion: Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy. [ABSTRACT FROM AUTHOR]- Published
- 2020
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24. Chronic intermittent hypoxia enhances disease progression in myelomaresistant mice.
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Ali, Mahmoud, Kowkuntla, Sandeep, Delloro, Derick J., Galambos, Csaba, Hathi, Deep, Janz, Siegfried, Shokeen, Monica, Tripathi, Chakrapani, Xu, Hongwei, Yuk, Jisung, Zhan, Fenghuang, Tomasson, Michael H., and Bates, Melissa L.
- Abstract
Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival (P 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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25. Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma.
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Gu, Chunyan, Jing, Xuefang, Holman, Carol, Sompallae, Ramakrishna, Zhan, Fenghuang, Tricot, Guido, Yang, Ye, and Janz, Siegfried
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- *
MULTIPLE myeloma treatment , *CANCER relapse , *MULTIPLE myeloma diagnosis , *DOXORUBICIN , *GENE expression - Abstract
Background: Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox).Methods: FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting.Results: Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9-5.6 fold) and Dox (1.5-2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively.Conclusions: These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels. [ABSTRACT FROM AUTHOR]- Published
- 2018
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26. RIP1 Cleavage in the Kinase Domain Regulates TRAIL-Induced NF-κB Activation and Lymphoma Survival.
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Zhang, Laiqun, Blackwell, Ken, Workman, Lauren M., Chen, Songhai, Pope, Marshall R., Janz, Siegfried, and Habelhah, Hasem
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ANTINEOPLASTIC agents , *CASPASES , *CANCER invasiveness , *APOPTOSIS , *TUMOR necrosis factors , *LYMPHOMA treatment - Abstract
Although TRAIL is considered a potential anticancer agent, it enhances tumor progression by activating NF-κB in apoptosis-resistant cells. Cellular FLICE-like inhibitory protein (cFLIP) overexpression and caspase-8 activation have been implicated in TRAIL-induced NF-κB activation; however, the underlying mechanisms are unknown. Here, we report that caspase-8-dependent cleavage of RIP1 in the kinase domain (KD) and intermediate domain (ID) determines the activation state of the NF-κB pathway in response to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment. In apoptosis-sensitive cells, caspase-8 cleaves RIP1 in the KD and ID immediately after the recruitment of RIP1 to the receptor complex, impairing IκB kinase (IKK) recruitment and NF-κB activation. In apoptosis-resistant cells, cFLIP restricts caspase-8 activity, resulting in limited RIP1 cleavage and generation of a KD-cleaved fragment capable of activating NF-κB but not apoptosis. Notably, depletion of the cytoplasmic pool of TRAF2 and cIAP1 in lymphomas by CD40 ligation inhibits basal RIP1 ubiquitination but does not prompt cell death, due to CD40L-induced cFLIP expression and limited RIP1 cleavage. Inhibition of RIP1 cleavage at the KD suppresses NF-κB activation and cell survival even in cFLIP-overexpressing lymphomas. Importantly, RIP1 is constitutively cleaved in human and mouse lymphomas, suggesting that cFLIP-mediated and caspase-8-dependent limited cleavage of RIP1 is a new layer of mechanism that promotes NF-κB activation and lymphoma survival. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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27. CDKN1A and FANCD2 are potential oncotargets in Burkitt lymphoma and multiple myeloma.
- Author
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Seong-Su Han, Tompkins, Van S., Dong-Ju Son, Sangwoo Han, Hwakyung Yun, Kamberos, Natalie L., Dehoedt, Casey L., Chunyan Gu, Holman, Carol, Tricot, Guido, Fenghuang Zhan, and Janz, Siegfried
- Subjects
- *
BURKITT'S lymphoma , *MULTIPLE myeloma , *CANCER treatment - Abstract
Background: Comparative genetic and biological studies on malignant tumor counterparts in human beings and laboratory mice may be powerful gene discovery tools for blood cancers, including neoplasms of mature B-lymphocytes and plasma cells such as Burkitt lymphoma (BL) and multiple myeloma (MM). Methods: We used EMSA to detect constitutive NF-κB/STAT3 activity in BL- and MM-like neoplasms that spontaneously developed in single-transgenic IL6 (interleukin-6) or MYC (c-Myc) mice, or in double-transgenic IL6MYC mice. qPCR measurements and analysis of clinical BL and MM datasets were employed to validate candidate NF-κB/STAT3 target genes. Results: qPCR demonstrated that IL6- and/or MYC-dependent neoplasms in mice invariably contain elevated mRNA levels of the NF-κB target genes, Cdkn1a and Fancd2. Clinical studies on human CDKN1A, which encodes the cell cycle inhibitor and tumor suppressor p21, revealed that high p21 message predicts poor therapy response and survival in BL patients. Similarly, up-regulation of FANCD2, which encodes a key member of the Fanconi anemia and breast cancer pathway of DNA repair, was associated with poor outcome of patients with MM, particularly those with high-risk disease. Conclusions: Our findings suggest that CDKN1A and FANCD2 are potential oncotargets in BL and MM, respectively. Additionally, the IL-6- and/or MYC-driven mouse models of human BL and MM used in this study may lend themselves to the biological validation of CDKN1A and FANCD2 as molecular targets for new approaches to cancer therapy and prevention. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
28. CDKN1A and FANCD2 are potential oncotargets in Burkitt lymphoma and multiple myeloma.
- Author
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Seong-Su Han, Tompkins, Van S., Dong-Ju Son, Sangwoo Han, Hwakyung Yun, Kamberos, Natalie L., Dehoedt, Casey L., Chunyan Gu, Holman, Carol, Tricot, Guido, Fenghuang Zhan, and Janz, Siegfried
- Subjects
- *
BURKITT'S lymphoma , *MULTIPLE myeloma , *INTERLEUKIN-6 , *LYMPHOMAS , *CYCLIN-dependent kinase inhibitors , *DNA repair , *GENETICS - Abstract
Background: Comparative genetic and biological studies on malignant tumor counterparts in human beings and laboratory mice may be powerful gene discovery tools for blood cancers, including neoplasms of mature B-lymphocytes and plasma cells such as Burkitt lymphoma (BL) and multiple myeloma (MM). Methods: We used EMSA to detect constitutive NF-κB/STAT3 activity in BL- and MM-like neoplasms that spontaneously developed in single-transgenic IL6 (interleukin-6) or MYC (c-Myc) mice, or in double-transgenic IL6MYC mice. qPCR measurements and analysis of clinical BL and MM datasets were employed to validate candidate NF-κB/STAT3 target genes. Results: qPCR demonstrated that IL6- and/or MYC-dependent neoplasms in mice invariably contain elevated mRNA levels of the NF-κB target genes, Cdkn1a and Fancd2. Clinical studies on human CDKN1A, which encodes the cell cycle inhibitor and tumor suppressor p21, revealed that high p21 message predicts poor therapy response and survival in BL patients. Similarly, up-regulation of FANCD2, which encodes a key member of the Fanconi anemia and breast cancer pathway of DNA repair, was associated with poor outcome of patients with MM, particularly those with high-risk disease. Conclusions: Our findings suggest that CDKN1A and FANCD2 are potential oncotargets in BL and MM, respectively. Additionally, the IL-6- and/or MYC-driven mouse models of human BL and MM used in this study may lend themselves to the biological validation of CDKN1A and FANCD2 as molecular targets for new approaches to cancer therapy and prevention. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
29. Bruton Tyrosine Kinase Is a Therapeutic Target in Stem-like Cells from Multiple Myeloma.
- Author
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Ye Yang, Jumei Shi, Zhimin Gu, Salama, Mohamed E., Das, Satyabrata, Wendlandt, Erik, Hongwei Xu, Junwei Huang, Yi Tao, Mu Hao, Franqui, Reinaldo, Levasseur, Dana, Janz, Siegfried, Tricot, Guido, and Fenghuang Zhan
- Subjects
- *
PROTEIN-tyrosine kinases , *MULTIPLE myeloma treatment , *CELL lines , *STEM cell research , *TUMOR growth - Abstract
Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma, yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population cells from human myeloma cell lines and multiple myeloma primary samples as surrogate for the elusive multiple myeloma stem cell, we found that elevated expression of BTK in myeloma cells leads to AKT/WNT/β-catenin-dependent upregulation of key stemness genes (OCT4, SOX2, NANOG, and MYC) and enhanced self-renewal. Enforced transgenic expression of BTK in myeloma cells increased features of cancer stemness, including clonogenicity and resistance to widely used myeloma drugs, whereas inducible knockdown of BTK abolished them. Furthermore, overexpression of BTK in myeloma cells promoted tumor growth in laboratory mice and rendered side population- derived tumors that contained high levels of BTK more sensitive to the selective, second-generation BTK inhibitor, CGI1746, than side population-derived tumors that harbored low levels of BTK. Taken together, these findings implicate BTK as a positive regulator of myeloma stemness and provide additional support for the clinical testing of BTK-targeted therapies in patients with myeloma. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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30. Waveguide sub-wavelength structures: a review of principles and applications.
- Author
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Halir, Robert, Bock, Przemek J., Cheben, Pavel, Ortega‐Moñux, Alejandro, Alonso‐Ramos, Carlos, Schmid, Jens H., Lapointe, Jean, Xu, Dan‐Xia, Wangüemert‐Pérez, J. Gonzalo, Molina‐Fernández, Íñigo, and Janz, Siegfried
- Subjects
- *
WAVEGUIDES , *WAVELENGTHS , *PHOTONICS , *REFLECTIVE materials , *ELECTROMAGNETIC waves , *POLARIZATION of radio waves - Abstract
Periodic structures with a sub-wavelength pitch have been known since Hertz conducted his first experiments on the polarization of electromagnetic waves. While the use of these structures in waveguide optics was proposed in the 1990s, it has been with the more recent developments of silicon photonics and high-precision lithography techniques that sub-wavelength structures have found widespread application in the field of photonics. This review first provides an introduction to the physics of sub-wavelength structures. An overview of the applications of sub-wavelength structures is then given including: anti-reflective coatings, polarization rotators, high-efficiency fiber-chip couplers, spectrometers, high-reflectivity mirrors, athermal waveguides, multimode interference couplers, and dispersion engineered, ultra-broadband waveguide couplers among others. Particular attention is paid to providing insight into the design strategies for these devices. The concluding remarks provide an outlook on the future development of sub-wavelength structures and their impact in photonics. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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31. A new model of LMP1-MYC interaction in B cell lymphoma.
- Author
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Ontiveros, Evelena P., Halwani, Ahmad, Stunz, Laura L., Kamberos, Natalie, Olivier, Alicia K., Janz, Siegfried, and Bishop, Gail A.
- Subjects
- *
CELL communication , *B cells , *LYMPHOMAS , *MEMBRANE proteins , *ONCOGENIC proteins - Abstract
Epstein-Barr virus (EBV) is associated with aggressive B cell lymphomas (BCLs). Latent membrane protein 1 (LMP1) of EBV is an oncogenic protein required for EBV B cell transformation. However, LMP1 is a weak oncogene in mice. Mice expressing Myc inserted 5' of the Eμ enhancer (iMycEμ), mimicking the t(8;14) translocation of endemic Burkitt lymphoma, develop delayed onset BCLs. To investigate potential cooperation between LMP1 and oncogenic MYC, we produced mice expressing the LMP1 signaling domain via a hybrid CD40-LMP1 transgene (mCD40-LMP1), and the dysregulated MYC protein of aggressive EBV+ BCLs. mCD40-LMP1/iMycEμ mice trended toward earlier BCL onset. BCLs from mCD40-LMP1/iMycEμ mice expressed LMP1 and were transplantable into immunocompetent recipients. iMycEμ and mCD40-LMP1/iMycEμ mice developed BCLs with similar immunophenotypes. LMP1 signaling was intact in BCLs as shown by inducible interleukin-6. Additionally, LMP1 signaling to tumor cells induced the two isoforms of Pim1, a constitutively active prosurvival kinase implicated in lymphomagenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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32. High-efficiency single etch step apodized surface grating coupler using subwavelength structure.
- Author
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Benedikovic, Daniel, Cheben, Pavel, Schmid, Jens H., Xu, Dan‐Xia, Lapointe, Jean, Wang, Shurui, Halir, Robert, Ortega‐Moñux, Alejandro, Janz, Siegfried, and Dado, Milan
- Subjects
- *
INTEGRATED optics , *OPTICAL gratings , *APODIZATION , *OPTICAL fibers , *SILICON-on-insulator technology - Abstract
Grating couplers are key elements enabling the coupling of light between planar waveguide circuits and optical fibers. In this work, it is demonstrated using simulations and experiments that a high coupling efficiency can be achieved for an arbitrary buried oxide thickness by judicious adjustment of the grating radiation angle. The coupler strength is engineered by subwavelength structure, allowing straightforward apodization and single etch step fabrication. The design has been implemented using Fourier-eigenmode expansion and finite difference time domain methods. The measured coupling loss of a continuously apodized grating is -2.16 dB with a 3 dB bandwidth of 64 nm, therefore opening promising prospects for low-cost and high-volume fabrication using 193 nm deep-ultraviolet lithography. It is also shown by simulations that a coupling loss as low as -0.42 dB is predicted for a modified coupler structure with bottom mirror. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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33. NIAM-Deficient Mice Are Predisposed to the Development of Proliferative Lesions including B-Cell Lymphomas.
- Author
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Reed, Sara M., Hagen, Jussara, Muniz, Viviane P., Rosean, Timothy R., Borcherding, Nick, Sciegienka, Sebastian, Goeken, J. Adam, Naumann, Paul W., Zhang, Weizhou, Tompkins, Van S., Janz, Siegfried, Meyerholz, David K., and Quelle, Dawn E.
- Subjects
- *
LYMPHOMAS , *ADP ribosylation factor 1 , *UBIQUITIN ligases , *CELL proliferation , *TUMOR suppressor genes , *GALACTOSIDASES , *GENE expression , *LABORATORY mice - Abstract
Nuclear Interactor of ARF and Mdm2 (NIAM, gene designation Tbrg1) is a largely unstudied inhibitor of cell proliferation that helps maintain chromosomal stability. It is a novel activator of the ARF-Mdm2-Tip60-p53 tumor suppressor pathway as well as other undefined pathways important for genome maintenance. To examine its predicted role as a tumor suppressor, we generated NIAM mutant (NIAMm/m) mice homozygous for a β-galactosidase expressing gene-trap cassette in the endogenous gene. The mutant mice expressed significantly lower levels of NIAM protein in tissues compared to wild-type animals. Fifty percent of aged NIAM deficient mice (14 to 21 months) developed proliferative lesions, including a uterine hemangioma, pulmonary papillary adenoma, and a Harderian gland adenoma. No age-matched wild-type or NIAM+/m heterozygous animals developed lesions. In the spleen, NIAMm/m mice had prominent white pulp expansion which correlated with enhanced increased reactive lymphoid hyperplasia and evidence of systemic inflammation. Notably, 17% of NIAM mutant mice had splenic white pulp features indicating early B-cell lymphoma. This correlated with selective expansion of marginal zone B cells in the spleens of younger, tumor-free NIAM-deficient mice. Unexpectedly, basal p53 expression and activity was largely unaffected by NIAM loss in isolated splenic B cells. In sum, NIAM down-regulation in vivo results in a significant predisposition to developing benign tumors or early stage cancers. These mice represent an outstanding platform for dissecting NIAM's role in tumorigenesis and various anti-cancer pathways, including p53 signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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34. Subwavelength grating Fourier-transform interferometer array in silicon-on-insulator.
- Author
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Bock, Przemek J., Cheben, Pavel, Velasco, Aitor V., Schmid, Jens H., Delâge, André, Florjańczyk, Mirosław, Lapointe, Jean, Xu, Dan‐Xia, Vachon, Martin, Janz, Siegfried, and Calvo, María L.
- Subjects
- *
FOURIER transform spectrometers , *INTERFEROMETERS , *DIFFRACTION gratings , *OPTICAL waveguides , *SPECTRUM analysis - Abstract
A planar waveguide Fourier-transform spectrometer with densely arrayed Mach-Zehnder interferometers is demonstrated. Subwavelength gratings are used to produce an optical path difference without waveguide bends. The fabricated device comprises of an array of 32 Mach-Zehnder interferometers, which produce a spatial interferogram without any moving parts, yielding a spectral resolution of 50 pm and a free-spectral range of 0.78 nm. As a result of similar propagation losses in subwavelength grating waveguides and conventional strip waveguides, loss imbalance is minimized and high interferometic extinction ratio of −25 to −30 dB is obtained. Furthermore, phase and amplitude errors arising from normal fabrication variation are compensated by the spectral retrieval process using calibration measurements. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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35. Piperlongumine inhibits LMP1/MYC-dependent mouse B-lymphoma cells.
- Author
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Han, Seong-Su, Tompkins, Van S., Son, Dong-Ju, Kamberos, Natalie L., Stunz, Laura L., Halwani, Ahmad, Bishop, Gail A., and Janz, Siegfried
- Subjects
- *
BLACK pepper (Plant) , *MEDICAL botany , *MYC proteins , *LYMPHOMAS in animals , *B cells , *BURKITT'S lymphoma , *LABORATORY mice , *THERAPEUTICS - Abstract
Highlights: [•] Mouse model of human Burkitt lymphoma revealed cancer inhibition by PL. [•] Treatment with PL led to apoptosis of malignant but not normal B cells. [•] PL inhibited LMP1–NF-κB–Myc-dependent target genes including p21-encoding Cdkn1a. [•] PL holds promise for new interventions approaches to hematologic malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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- View/download PDF
36. Espectrómetro de transformada de Fourier implementado mediante guías de onda en espiral con base de silicio.
- Author
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Velasco, Aitor V., Calvo, María L., Cheben, Pavel, Bock, Przemek, Schmid, Jens H., Lapointe, Jean, Delâge, André, Janz, Siegfried, Dan-Xia Xu, and Florjańczyk, Mirosław
- Abstract
In this work we present the design, fabrication and characterization of a Fourier-Transform micro-spectrometer implemented with planar waveguides. The device comprises an array of 32 Mach-Zehnder interferometers with increasing optical path differences between the arms of the interferometer, reaching a resolution of 0.1 nm in a free spectral range of 1.6 nm. Silicon waveguides in a spiral structure have been used in the arms of the interferometer, reducing the footprint of the device below 12 mm². [ABSTRACT FROM AUTHOR]
- Published
- 2013
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37. An ultra-compact multimode interference coupler with a subwavelength grating slot.
- Author
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Ortega‐Moñux, Alejandro, Alonso‐Ramos, Carlos, Maese‐Novo, Alejandro, Halir, Robert, Zavargo‐Peche, Luis, Pérez‐Galacho, Diego, Molina‐Fernández, Iñigo, Wangüemert‐Pérez, J. Gonzalo, Cheben, Pavel, Schmid, Jens H., Lapointe, Jean, Xu, Danxia, and Janz, Siegfried
- Abstract
Multimode interference couplers (MMIs) are fundamental building blocks in photonic integrated circuits. Here it is experimentally demonstrated, for the first time, a two-fold length reduction in an MMI coupler without any penalty on device performance. The design is based on a slotted 2 × 2 MMI fabricated on a commercial silicon-on-insulator (SOI) substrate. The slot is implemented with a subwavelength grating (SWG) comprising holes fully etched down to the oxide cladding, thereby allowing single etch step fabrication. The device has been designed using an in-house tool based on the Fourier Eigenmode Expansion Method. It has a footprint of only 3.5 μm x 23 μm and it exhibits a measured extinction ratio better than 15 dB within the full C-band (1530 nm-1570 nm). SWG engineered slots thus offer excellent perspectives for the practical realization of MMIs couplers with substantially reduced footprint yet with outstanding performance. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
38. Piperlongumine inhibits proliferation and survival of Burkitt lymphoma in vitro
- Author
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Han, Seong-Su, Son, Dong-Ju, Yun, Hwakyung, Kamberos, Natalie L., and Janz, Siegfried
- Subjects
- *
BURKITT'S lymphoma , *CELL proliferation , *INDIAN long pepper , *BLACK pepper (Plant) , *ALKALOIDS , *B cells , *CELL lines , *CHROMOSOMAL translocation , *REACTIVE oxygen species - Abstract
Abstract: Piperlongumine (PL), a pepper plant alkaloid from Piper longum, kills solid tumor cells in a highly selective, potent fashion. To evaluate whether PL may have similar effects on malignant blood cells, we determined the efficacy with which PL inhibits the B-lymphocyte derived neoplasm, Burkitt lymphoma (BL). Low micromolar concentrations of PL (IC50 =2.8μM×8.5μM) curbed growth and survival of two EBV+ BL cell lines (Daudi, Raji) and two EBV BL cell lines (Ramos, DG-75), but left normal peripheral blood B-lymphocytes unharmed. PL-dependent cytotoxicity was effected in part by reduced NF-κB and MYC activity, with the former being caused by inhibition of IκBα degradation, nuclear translocation of p65, and binding of NF-κB dimers to cognate DNA sequences in gene promoters. In 4 of 4 BL cell lines, the NF-κB/MYC-regulated cellular target genes, E2F1 and MYB, were down regulated, while the stress sensor gene, GADD45B, was up regulated. The EBV-encoded oncogene, LMP-1, was suppressed in Daudi and Raji cells. Considering that NF-κB, MYC and LMP-1 play a crucial role in the biology of many blood cancers including BL, our results provide a strong preclinical rationale for considering PL in new intervention approaches for patients with hematologic malignancies. [Copyright &y& Elsevier]
- Published
- 2013
- Full Text
- View/download PDF
39. Development of a Fourier-transform waveguide spectrometer for space applications.
- Author
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Florjańczyk, Mirosław, Alonso-Ramos, Carlos, Bock, Przemek, Bogdanov, Alexei, Cheben, Pavel, Molina-Fernández, Íñigo, Janz, Siegfried, Lamontagne, Boris, Ortega-Moñux, Alejandro, Scott, Alan, Sinclair, Kenneth, Solheim, Brian, and Xu, Dan-Xia
- Subjects
- *
FOURIER transforms , *WAVEGUIDES , *WATER vapor , *ENERGY bands , *INTERFEROMETERS , *SILICON-on-insulator technology , *DIFFRACTION gratings - Abstract
We describe the development of a waveguide Fourier-transform spectrometer for space-borne high-resolution sensing. A prototype device is designed to monitor the water vapor absorption band near 1,364 nm with a resolution of 0.05 nm. It has no moving parts and is based on a unique concept of arrayed interferometers implemented in silicon-on-insulator planar waveguide chip. The optical input is formed by many independent waveguides, providing a significantly increased light gathering capability (étendue) compared to single-waveguide input configurations. Enhancements of the spectrometer capabilities are achieved by stacking planar waveguide layers and by using surface gratings to couple light into the waveguides. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
40. HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice.
- Author
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Suthaus, Jan, Stuhlmann-Laeisz, Christiane, Tompkins, Van S., Rosean, Timothy R., Klapper, Wolfram, Tosato, Giovanna, Janz, Siegfried, Scheller, Jürgen, and Rose-John, Stefan
- Subjects
- *
HUMAN herpesvirus-6 , *INTERLEUKIN-6 , *LABORATORY mice , *CASTLEMAN'S disease , *KAPOSI'S sarcoma , *LYMPHOMAS , *MHC antibodies - Abstract
Human herpes virus 8 (HHV-8) or Kaposi sarcoma-associated herpes virus is the etiologic agent of Kaposi sarcoma, primary effusion lymphoma, and plasma cell-type multicentric Castleman disease (MCD). HHV-8 encodes a viral homolog of human IL-6, called viral IL-6 (vlL-6), which does not require the cellular IL-6 receptor for binding to the ubiquitously expressed gp130 receptor subunit and subsequent JAK-STAT signaling. Thus, in contrast to IL-6, vlL-6 can stimulate virtually all cells in the body. To elucidate the mechanism by which vlL-6 drives human diseases, we generated transgenic mice that consti-tutively express vlL-6 under control of the MHC class I promoter. The mice were found to exhibit vlL-6 serum levels comparable with those observed in HHV-8-infected patients, to contain elevated amounts of phosphorylated STAT3 in spleen and lymph nodes, where vlL-6 was produced, and to spontaneously develop key features of human plasma cell-type MCD, including splenomegaly, multifocal lymphadenopathy, hypergammaglobulinemia, and plasmacytosis. Transfer of the vlL-6 transgene onto an /L-6-def icient genetic background abrogated MCD-like phe-noty pes, indicating that endogenous mouse IL-6 is a crucial cofactor in the natural history of the disease. Our results in mice suggest that human IL-6 plays an important role in the pathogenesis of HHV-8-associated MCD. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
41. Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms.
- Author
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Chen-Feng Qi, Yong-Soo Kim, Shao Xiang, Abdullaev, Ziedulla, Torrey, Ted A., Janz, Siegfried, Kovalchuk, Alexander L., Jiafang Sun, Delin Chen, Cho, William C., Wei Gu, and Morse III, Herbert C.
- Subjects
- *
B cell lymphoma , *ENZYME activation , *GENETIC transcription , *UBIQUITIN ligases , *APOPTOSIS , *GENETIC code , *CANCER cells , *DNA-binding proteins - Abstract
Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both the MYC and the ARF-p53 signaling pathways, prompting us to determine if it is involved in the pathogenesis of MYC-driven B cell lymphomas. ARF-BP1 was expressed at high levels in cell lines from lymphomas with either wild type or mutated p53 but not in ARF-deficient cells. Downregulation of ARF-BP1 resulted in elevated steady state levels of p53, growth arrest and apoptosis. Co-immunoprecipitation studies identified a multiprotein complex comprised of ARF-BP1, ARF, p53, MYC and the multifunctional DNA-binding factor, CTCF, which is involved in the transcriptional regulation of MYC, p53 and ARF. ARF-BP1 bound and ubiquitylated CTCF leading to its proteasomal degradation. ARF-BP1 and CTCF thus appear to be key cofactors linking the MYC proliferative and p53-ARF apoptotic pathways. In addition, ARF-BP1 could be a therapeutic target for MYC-driven B lineage neoplasms, even if p53 is inactive, with inhibition reducing the transcriptional activity of MYC for its target genes and stabilizing the apoptosis-promoting activities of p53. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
42. Global gene expression profiling in mouse plasma cell tumor precursor and bystander cells reveals potential intervention targets for plasma cell neoplasia.
- Author
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LeGrand, Jason, Eun Sung Park, Hongyang Wang, Gupta, Shalu, Owens Jr, James D., Nelson, Patrick J., DuBois, Wendy, Bair, Thomas, Janz, Siegfried, and Mushinski, J. Frederic
- Subjects
- *
GENE expression , *PLASMA cells , *CANCER invasiveness , *PROTEIN synthesis , *CELL tumors , *OSTEOPONTIN , *DNA microarrays - Abstract
Tumor progression usually proceeds through several sequential stages, any of which could be targets for interrupting the progression process if one understood these steps at the molecular level. We extracted nascent plasma cell tumor (PCT) cells from within inflammatory oil granulomas (OG) isolated from IP pristane-injected BALB/c.iMycEμ mice at 5 different time points during tumor progression. We used laser capture microdis-section to collect incipient PCT cells and analyzed their global gene expression on Affymetrix Mouse Genome 430A microar-rays. Two independent studies were performed with different sets of mice. Analysis of the expression data used ANOVA and Bayesian estimation of temporal regulation. Genetic pathway analysis was performed using MetaCore (GeneGo) and IPA (Ingenuity). The gene expression profiles of PCT samples and those of undis-sected OG samples from adjacent sections showed that different genes and pathways were mobilized in the tumor cells during tumor progression, compared with their stroma. Our analysis implicated several genetic pathways in PCT progression, including biphasic (up-and then down-regulation) of the Sppl/osteopontin-dependent network and up-regulation of mRNA translation/protein synthesis. The latter led to a biologic validation study that showed that the AMPK-activating diabetes drug, metformin, was a potent specific PCT inhibitor in vitro. (Blood. 2012;119(4):1018-1028) [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
43. A novel wavelength dispersive device with a dispersive element based on staircase-like straight and parallel arrayed waveguides
- Author
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Martínez Matos, Oscar, Calvo, María L., Cheben, Pavel, Janz, Siegfried, Rodrigo, José A., Xu, Dan-Xia, and Delâge, André
- Subjects
- *
WAVEGUIDES , *SILICON-on-insulator technology , *WAVELENGTH division multiplexing , *OPTICAL communications - Abstract
Abstract: We propose a new type of arrayed waveguide grating (AWG) multiplexer/demultiplexer based on modified group refractive index. This device is composed by an array of straight and parallel waveguides of equal length and each waveguide consist of two sections with different width. The length of the two sections are changed from a waveguide to the adjacent one following a linear dependence resulting in a wavelength dispersive waveguide array. An example of the device design for silicon-on-insulator (SOI) platform is provided and numerical simulations have been carried out for various arrayed waveguide parameters. We demonstrate that the group index modification can be used for tailoring device dispersion properties, and that it can also result in new dispersion characteristics predicted numerically not observed in conventional AWGs. Additional advantages are that the demultiplexer does not necessarily require bending waveguide sections as in a conventional AWG (de)multiplexers, and thus yields highly compact devices with potentially very low insertion loss. Channel spacing of 1nm have been predicted for sub-micron waveguides sizes. In this paper it is also proposed a novel wavefront converter based on waveguide array lens-like element with waveguides broadened sections. Numerical results for different input/output geometries are analized. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
44. Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia.
- Author
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Eun Sung Park, Shaughnessy Jr, John D, Gupta, Shalu, Hongyang Wang, Ju-Seog Lee, Hyun Goo Woo, Fenghuang Zhan, Owens Jr, James D, Potter, Michael, Janz, Siegfried, and Mushinski, J Frederic
- Subjects
- *
LYMPHOMAS , *GENETIC regulation , *GENE expression , *TUMORS , *B cells - Abstract
Background: To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B-cell lymphomas and six subtypes of pristane-induced mouse plasma cell tumors, three of which developed much earlier than the others. Results: Unsupervised hierarchical cluster analysis exhibited two main sub-clusters of samples: a B-cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e.g., ABPCs, plasma cell tumors that contained typical T(12;15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6;15) translocations, in which the breakpoint was in the Pvt-1 locus, 230 kb 3' of c-Myc, suggesting that c-Myc activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed Socs1 and Socs2 but v-Abl-accelerated plasma cell tumors expressed 4-5 times as much. Both v-Abl-accelerated and non-v-Abl-associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI-571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v-Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors. Conclusion: Gene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-Myc-activating chromosome translocation. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
45. CDDO-Imidazolide inhibits growth and survival of c-Myc-induced mouse B cell and plasma cell neoplasms.
- Author
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Seong-Su Han, Liangping Peng, Seung-Tae Chung, DuBois, Wendy, Sung-Ho Maeng, Shaffer, Arthur L., Sporn, Michael B., and Janz, Siegfried
- Subjects
- *
TUMORS , *PLASMA cell diseases , *LYMPHOMAS , *CYTOLOGY , *CANCER treatment , *CANCER research - Abstract
Background: Gene-targeted iMycEμ mice that carry a His6-tagged mouse Myc(c-myc)cDNA, MycHis, just 5' of the immunoglobulin heavy-chain enhancer, Eμ, are prone to B cell and plasma cell neoplasms, such as lymphoblastic B-cell lymphoma (LBL) and plasmacytoma (PCT). Cell lines derived from Myc-induced neoplasms of this sort may provide a good model system for the design and testing of new approaches to prevent and treat MYC-driven B cell and plasma cell neoplasms in human beings. To test this hypothesis, we used the LBL-derived cell line, iMycEμ-1, and the newly established PCT-derived cell line, iMycEμ-2, to evaluate the growth inhibitory and death inducing potency of the cancer drug candidate, CDDO-imidazolide (CDDO-Im). Methods: Morphological features and surface marker expression of iMycEμ-2 cells were evaluated using cytological methods and FACS, respectively. mRNA expression levels of the inserted MycHis and normal Myc genes were determined by allele-specific RT-PCR and qPCR. Myc protein was detected by immunoblotting. Cell cycle progression and apoptosis were analyzed by FACS. The expression of 384 "pathway" genes was assessed with the help of Superarray© cDNA macroarrays and verified, in part, by RT-PCR. Results: Sub-micromolar concentrations of CDDO-Im caused growth arrest and apoptosis in iMycEμ-1 and iMycEμ-2 cells. CDDO-Im-dependent growth inhibition and apoptosis were associated in both cell lines with the up-regulation of 30 genes involved in apoptosis, cell cycling, NF.B signaling, and stress and toxicity responses. Strongly induced (=10 fold) were genes encoding caspase 14, heme oxygenase 1 (Hmox1), flavin-containing monooxygenase 4 (Fmo4), and three members of the cytochrome P450 subfamily 2 of mixed-function oxygenases (Cyp2a4, Cyp2b9, Cyp2c29). CDDO-Im-dependent gene induction coincided with a decrease in Myc protein. Conclusion: Growth arrest and killing of neoplastic mouse B cells and plasma cells by CDDO-Im, a closely related derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid, appears to be caused, in part, by drug-induced stress responses and reduction of Myc. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
46. Molecular and cytological features of the mouse B-cell lymphoma line iMycEμ-1.
- Author
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Han, Seong Su, Shaffer, Arthur L., Peng, Liangping, Chung, Seung Tae, Lim, Jae Hwan, Maeng, Sungho, Kim, Joong Su, McNeil, Nicole, Ried, Thomas, Staudt, Louis M., and Janz, Siegfried
- Subjects
- *
MYC oncogenes , *LYMPHOMAS , *PLASMA cells , *MICE , *GENE expression - Abstract
Background: Myc-induced lymphoblastic B-cell lymphoma (LBL) in iMycEμmice may provide a model system for the study of the mechanism by which human MYC facilitates the initiation and progression of B cell and plasma cell neoplasms in human beings. We have recently shown that gene-targeted iMycEμ mice that carry a His6-tagged mouse Myc cDNA, MycHis, just 5' of the immunoglobulin heavy-chain enhancer, Eμ, are prone to B cell and plasma cell tumors. The predominant tumor (∼50%) that arose in the iMycEμ mice on the mixed genetic background of segregating C57BL/6 and 129/SvJ alleles was LBL. The purpose of this study was to establish and characterize a cell line, designated iMycEμ-1, for the in-depth evaluation of LBL in vitro. Methods: The morphological features and the surface marker expression profile of the iMycEμ-1 cells were evaluated using cytological methods and FACS, respectively. The cytogenetic make-up of the iMycEμ-1 cells was assessed by spectral karyotyping (SKY). The expression of the inserted MycHis gene was determined using RT-PCR and qPCR. Clonotypic immunoglobulin gene arrangements were detected by Southern blotting. The global gene expression program of the iMycEμ-1 cells and the expression of 768 "pathway" genes were determined with the help of the Mouse Lymphochip© and Superarray© cDNA micro- and macroarrays, respectively. Array results were verified, in part, by RT-PCR and qPCR. Results: Consistent with their derivation from LBL, the iMycEμ-1 cells were found to be neoplastic IgMhighIgDlow lymphoblasts that expressed typical B-cell surface markers including CD40, CD54 (ICAM -1), CD80 (B7-1) and CD86 (B7-2). The iMycEμ-1 cells harbored a reciprocal T(9;11) and three non-reciprocal chromosomal translocations, overexpressed MycHis at the expense of normal Myc, and exhibited gene expression changes on Mouse Lymphochip© microarrays that were consistent with MycHis-driven B-cell neoplasia. Upon comparison to normal B cells using eight different Superarray© cDNA macroarrays, the iMycEμ-1 cells showed the highest number of changes on the NF?B array. Conclusion: The iMycEμ-1 cells may provide a uniquely useful model system to study the growth and survival requirements of Myc-driven mouse LBL in vitro. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
47. Novel targeted deregulation of c-Myc cooperates with Bcl-XL to cause plasma cell neoplasms in mice.
- Author
-
Cheung, Wan Cheung, Kim, Joong Su, Linden, Michael, Peng, Liangping, Van Ness, Brian, Polakiewicz, Roberto O., and Janz, Siegfried
- Subjects
- *
MYELOMA proteins , *TRANSGENIC organisms , *ONCOLOGY , *IMMUNE system , *PROTEINS , *PLASMA cells - Abstract
Deregulated expression of both Myc and Bcl-XL are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-XL in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine- tagged mouse Myc gene, MycHis, into the mouse Ig heavy-chain Cα locus. We also generated Bcl-XL transgenic mice that contain a multicopy Flag-tagged mouse Bcl-xFlag transgene driven by the mouse Ig K light-chain 3' enhancer. Single-transgenic Bcl-XL mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-XL mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of MycHis and Bcl-XLFlag proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-XL mice. Our findings demonstrate that the enforced expression of Myc and Bcl-XL by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
48. Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice.
- Author
-
Cheung, Wan Cheung, Kim, Joong Su, Linden, Michael, Peng, Liangping, Van Ness, Brian, Polakiewicz, Roberto D, and Janz, Siegfried
- Subjects
- *
PROTEIN metabolism , *ANIMAL experimentation , *BONE marrow , *COMPARATIVE studies , *GENES , *LYMPH nodes , *RESEARCH methodology , *MEDICAL cooperation , *MICE , *MONOCLONAL antibodies , *PLASMACYTOMA , *PROTEINS , *RESEARCH , *RESEARCH funding , *SPLEEN , *EVALUATION research - Abstract
Deregulated expression of both Myc and Bcl-X(L) are consistent features of human plasma cell neoplasms (PCNs). To investigate whether targeted expression of Myc and Bcl-X(L) in mouse plasma cells might lead to an improved model of human PCN, we generated Myc transgenics by inserting a single-copy histidine-tagged mouse Myc gene, Myc(His), into the mouse Ig heavy-chain Calpha locus. We also generated Bcl-X(L) transgenic mice that contain a multicopy Flag-tagged mouse Bcl-x(Flag) transgene driven by the mouse Ig kappa light-chain 3' enhancer. Single-transgenic Bcl-X(L) mice remained tumor free by 380 days of age, whereas single-transgenic Myc mice developed B cell tumors infrequently (4 of 43, 9.3%). In contrast, double-transgenic Myc/Bcl-X(L) mice developed plasma cell tumors with short onset (135 days on average) and full penetrance (100% tumor incidence). These tumors produced monoclonal Ig, infiltrated the bone marrow, and contained elevated amounts of Myc(His) and Bcl-X(L)(Flag) proteins compared with the plasma cells that accumulated in large numbers in young tumor-free Myc/Bcl-X(L) mice. Our findings demonstrate that the enforced expression of Myc and Bcl-X(L) by Ig enhancers with peak activity in plasma cells generates a mouse model of human PCN that recapitulates some features of human multiple myeloma. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
49. Bcl-2 reduces mutant rates in a transgenic lacZ reporter gene in mouse pre-B lymphocytes
- Author
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Felix, Klaus, Rolink, Antonius, Melchers, Fritz, and Janz, Siegfried
- Subjects
- *
MUTAGENESIS , *LYMPHOCYTES , *IONIZING radiation - Abstract
To assess mutagenesis during early B-lymphocyte development in vitro, progenitor B cells (pre-B cells) were obtained from fetal livers of BALB/c mice and DBA/2N mice that harbored the transgenic shuttle vector, pUR288, with a lacZ reporter gene for the determination of mutant frequencies (MFs). Differentiation-arrested pre-B cells demonstrated a marked dose-dependent increase in lacZ mutant levels after exposure to γ-irradiation with a peak MF of
250×10−5 at 2.5 Gy. Without genotoxic treatment, pre-B cells undergoing spontaneous differentiation into surface IgM expressing immature B cells exhibited lacZ mutant levels of up to95×10−5 . The mutational pattern was dominated in both experiments by illegitimate recombination mutations of lacZ, not point mutations. Likewise, in both experiments, the enforced expression of Bcl-2 resulted in a striking reduction of lacZ mutations. These findings indicated that mouse pre-B cells are prone to accumulate induced and self-inflicted mutations, particularly recombinations. Additionally, our studies revealed a heretofore unknown role of Bcl-2 in inhibiting mutagenesis during early B-cell development in mice. [Copyright &y& Elsevier]- Published
- 2003
- Full Text
- View/download PDF
50. Redox imbalance and mutagenesis in spleens of mice harboring a hypomorphic allele of Gpdxa encoding glucose 6-phosphate dehydrogenase
- Author
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Felix, Klaus, Rockwood, Lynne D., Pretsch, Walter, Bornkamm, Georg-Wilhelm, and Janz, Siegfried
- Subjects
- *
MUTAGENESIS , *FREE radicals - Abstract
Mice harboring the activity-attenuated Gpdxa-m2Neu allele and also harboring a chromosomally integrated lacZ reporter gene to study mutagenesis (pUR288) were used to demonstrate that moderate glucose 6-phosphate dehydrogenase (G6PD) deficiency causes elevated mutagenesis and endogenous oxidative stress in the spleen. G6PD-deficient spleens with a residual enzyme activity of 22% exhibited a dramatic shift in the mutational pattern of lacZ (4.6-fold increase in the prevalence of recombination mutations of lacZ) together with a 1.8-fold increase in mutant frequencies in lacZ. A concomitant 3-fold reduction in catalase activity (dependent upon NADPH) indicated that the in vivo supply of G6PD-generated NADPH was insufficient. An additional 3-fold increase in oxidized glutathione suggested that redox control was disturbed in G6PD-deficient spleens. These findings indicate that G6PD is required for limiting oxidative mutagenesis in the mouse spleen. Gpdxa-m2Neu is the first hypomorphic allele of a mouse housekeeping gene associated with elevated somatic mutagenesis in vivo. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
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