Biomedical subjects

Siegfried Janz

Publications and source records attributed to Siegfried Janz.

At least 19 recordsLinked to original sources

PubMed2006

Myc translocations in B cell and plasma cell neoplasms.

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 mu region (Smu), 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 Smu (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.

Animals↗

PubMed2006

CDDO-Imidazolide inhibits growth and survival of c-Myc-induced mouse B cell and plasma cell neoplasms.

BACKGROUND: Gene-targeted iMycEmu mice that carry a His6-tagged mouse Myc(c-myc)cDNA, MycHis, just 5' of the immunoglobulin heavy-chain enhancer, Emu, 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, iMycEmu-1, and the newly established PCT-derived cell line, iMycEmu-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 iMycEmu-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 iMycEmu-1 and iMycEmu-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, NFkappaB signaling, and stress and toxicity responses. Strongly induced (> or = 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.

Animals↗

PubMed2005

Optically reconfigurable azobenzene polymer-based fiber Bragg filter.

Optically writable, thermally erasable surface relief gratings in thin Disperse Red 1 polymethyl methacrylate azopolymer films were used to demonstrate an arbitrarily reconfigurable fiber Bragg filter. Gratings were optically written on azopolymer-coated side-polished fiber blocks, and a write-erase-write cycle was demonstrated. Finite difference time domain simulations reveal that this optically reconfigurable device concept can be optimized in a silicon-on-insulator waveguide platform.

Journal Article↗

PubMed2005

Molecular and cytological features of the mouse B-cell lymphoma line iMycEmu-1.

BACKGROUND: Myc-induced lymphoblastic B-cell lymphoma (LBL) in iMycEmu mice 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 iMycEmu mice that carry a His6-tagged mouse Myc cDNA, MycHis, just 5' of the immunoglobulin heavy-chain enhancer, Emu, are prone to B cell and plasma cell tumors. The predominant tumor (approximately 50%) that arose in the iMycEmu 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 iMycEmu-1, for the in-depth evaluation of LBL in vitro. METHODS: The morphological features and the surface marker expression profile of the iMycEmu-1 cells were evaluated using cytological methods and FACS, respectively. The cytogenetic make-up of the iMycEmu-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 iMycEmu-1 cells and the expression of 768 "pathway" genes were determined with the help of the Mouse Lymphochip(c) and Superarray(c) cDNA micro- and macroarrays, respectively. Array results were verified, in part, by RT-PCR and qPCR. RESULTS: Consistent with their derivation from LBL, the iMycEmu-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 iMycEmu-1 cells harbored a reciprocal T(9;11) and three non-reciprocal chromosomal translocations, over-expressed 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 iMycEmu-1 cells showed the highest number of changes on the NFkappaB array. CONCLUSION: The iMycEmu-1 cells may provide a uniquely useful model system to study the growth and survival requirements of Myc-driven mouse LBL in vitro.

Animals↗

PubMed2005

Insertion of Myc into Igh accelerates peritoneal plasmacytomas in mice.

Gene-targeted mice that contain a His6-tagged mouse c-Myc cDNA, Myc(His), inserted head to head into different sites of the mouse immunoglobulin heavy-chain locus, Igh, mimic the chromosomal T(12;15)(Igh-Myc) translocation that results in the activation of Myc in the great majority of mouse plasmacytomas. Mice carrying Myc(His) just 5' of the intronic heavy-chain enhancer Emu (strain iMyc(Emu)) provide a specific model of the type of T(12;15) found in a subset (approximately 20%) of plasmacytomas that develop "spontaneously" in the gut-associated lymphoid tissue (GALT) of interleukin-6 transgenic BALB/c (C) mice. Here we show that the transfer of the iMyc(Emu) transgene from a mixed genetic background of segregating C57BL/6 x 129/SvJ alleles to the background of C increased the incidence of GALT plasmacytomas by a factor of 2.5 in first-generation backcross mice (C.iMyc(Emu) N1). Third-generation backcross mice (C.iMyc(Emu) N3, approximately 94% C alleles) were hypersusceptible to inflammation-induced peritoneal plasmacytomas (tumor incidence, 100%; mean tumor onset, 86 +/- 28 days) compared with inbred C mice (tumor incidence, 5% on day 150 after tumor induction). Peritoneal plasmacytomas of C.iMyc(Emu) N3 mice overexpressed Myc(His), produced monoclonal immunoglobulin, and exhibited a unique plasma cell signature upon gene expression profiling on mouse Lymphochip cDNA microarrays. These findings indicated that the iMyc(Emu) transgene accelerates plasmacytoma development by collaborating with tumor susceptibility alleles of strain C and circumventing the requirement for tumor precursors to acquire deregulated Myc by chromosomal translocation.

Alleles↗

PubMed2005

Wavelength-dispersive device based on a Fourier-transform Michelson-type arrayed waveguide grating.

We propose a new type of arrayed waveguide grating (AWG) device that operates as a Fourier-transform (FT) spectrometer without the need of scanning elements. The large input aperture size typical of a FT spectrometer eliminates the requirement for a narrow single-mode input waveguide while still achieving high spectral resolution with a markedly increased light-gathering capability (etendue). An example of the device with a resolution of 0.07 nm (approximately 10 GHz) and designed for a silicon-on-insulator platform is presented. The calculated spectra show no noticeable deterioration for aperture widths as large as 40 microm, yielding more than a 50-fold increase in aperture size compared with conventional AWG or echelle grating based devices at the equivalent resolution.

Journal Article↗

PubMed2005

Uncovering MYC's full oncogenic potential in the hematopoietic system.

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. They report 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.

Animals↗

PubMed2005

Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice.

We used gene targeting in mice to insert a His(6)-tagged mouse c-Myc cDNA, Myc(His), head to head into the mouse immunoglobulin heavy-chain locus, Igh, just 5' of the intronic enhancer, Emu. The insertion of Myc(His) mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, Myc(His) transgenic mice developed B-cell and plasma neoplasms, such as IgM(+) lymphoblastic B-cell lymphomas, Bcl-6(+) diffuse large B-cell lymphomas, and CD138(+) plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc(His), and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of Myc(His), suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19(Arf)-Mdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc(His) insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Myc-activating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation.

Amino Acid Sequence↗

PubMed2005

Location of Myc, Igh, and Igk on Robertsonian fusion chromosomes is inconsequential for Myc translocations and plasmacytoma development in mice, but Rb(6.15)-carrying tumors prefer Igk-Myc inversions over translocations.

The location of the Myc and immunoglobulin (Ig) loci on metacentric Robertsonian (Rb) fusion chromosomes may affect the development of mouse plasmacytomas (Pcts) by changing the probability with which chromosomal Myc-Ig translocations occur. To test this hypothesis, we induced Pcts in BALB/c (C) mice that carried Rb(4.12) and/or Rb(6.15) chromosomes. The Rb mice developed Pcts (n = 198) with similar onset and incidence to that in the inbred C mice. Karyotyping of 70 Rb-carrying Pcts demonstrated that in these tumors, just as in their counterparts in inbred C mice, the Igh heavy-chain locus was translocated with Myc more often than was the Igk light-chain locus. Pcts harboring Igh or Igk on normal and Rb chromosomes showed no bias toward either in generating Myc translocations. These findings indicated that the location of Myc, Igh, and Igk on normal or Rb chromosomes is inconsequential for Myc translocation and Pct development. In contrast, in Rb(6.15) mice, in which chromosomal inversions competed with chromosomal translocations for Igk-Myc juxtapositions, the former occurred more frequently than the latter in the resulting Pcts. This suggested that spatial proximity of Igk and Myc on the same chromosome facilitates the rearrangement of these loci. Myc translocation-dependent mouse Pct may provide a good model system for furthering our understanding of the relationship of higher-order genome organization in the interphase nucleus, origin of chromosomal translocations, and development of cancer.

Animals↗

PubMed2005

Extraosseous IL-6 transgenic mouse plasmacytoma sometimes lacks Myc-activating chromosomal translocation.

The cellular oncogene MYC and plasma cell growth, differentiation, and survival factor IL-6 play critical roles in the natural history of human plasma cell neoplasms such as multiple myeloma (MM). Myc and IL-6 also are at the center of neoplastic plasma cell transformation in BALB/c mice that carry a human IL-6 transgene and, therefore, predictably develop plasmacytomas (PCTs). We showed previously that, much like advanced MM or human myeloma cell lines (HMCLs), in which MYC is frequently deregulated in cis because of complex cytogenetic aberrations juxtaposing MYC to immunoglobulin enhancers, IL-6 transgenic PCTs commonly deregulate Myc in cis by chromosomal translocation, predominantly T(12;15)(Igh-Myc). In this article, we show that, analogous to primary MM in which MYC is mostly deregulated in trans by signaling pathways converging at the MYC promoter, IL-6 transgenic PCTs sometimes develop in the absence of Myc translocations, thus activating Myc in trans. We present cytogenetic and molecular evidence on two IL-6 transgenic PCTs that contained overexpressed Myc protein but lacked T(12;15)(Igh-Myc) and two related Myc--deregulating translocations that juxtapose Myc to immunoglobulin light-chain instead of heavy-chain enhancers: T(6;15)(Igkappa-Pvt1) and T(15;16)(Pvt1-Iglambda). We conclude that Myc translocations are not strictly required for IL-6-driven PCT development in mice. IL-6 transgenic PCTs may provide a valuable model system for elucidating both trans and cis mechanisms of Myc deregulation of great relevance for MYC deregulation in human MM.

Animals↗

PubMed2004

Deregulated expression of the Myc cellular oncogene drives development of mouse "Burkitt-like" lymphomas from naive B cells.

Chromosomal translocations juxtaposing immunoglobulin (Ig) and MYC genes are the hallmarks of human Burkitt lymphoma (BL), with deregulated MYC expression being a critical factor in pathogenesis. By inserting an intact mouse Myc gene into the mouse genome, proximal to the Ig enhancer Emu, the effect of a precise mimic of the major t(8;14) translocation of human endemic BL (eBL) could be investigated. Knock-in mice developed IgM-positive B-cell tumors, with most being typical of eBL by histology and immunophenotype, including expression of the germinal center (GC)-associated protein, BCL6. Unlike eBL, however, analysis of Ig V(H) sequences revealed no significant level of somatic mutation. Thus, constitutive expression of Myc in the knock-in mice is apparently able to induce "Burkitt-like" lymphomas before antigen stimulation and formation of a GC. In contrast, human eBL development occurs in a GC or post-GC site with a likely contribution to pathogenesis from Epstein-Barr virus (EBV) and other epigenetic factors.

Animals↗

PubMed2004

Selenium deficiency abrogates inflammation-dependent plasma cell tumors in mice.

The role of the micronutrient, selenium, in human cancers associated with chronic inflammations and persistent infections is poorly understood. Peritoneal plasmacytomas (PCTs) in strain BALB/c (C), the premier experimental model of inflammation-dependent plasma cell transformation in mice, may afford an opportunity to gain additional insights into the significance of selenium in neoplastic development. Here, we report that selenium-depleted C mice (n = 32) maintained on a torula-based low-selenium diet (5-8 micro g of selenium/kg) were totally refractory to pristane induction of PCT. In contrast, 11 of 26 (42.3%) control mice maintained on a selenium adequate torula diet (300 micro g of selenium/kg) and 15 of 40 (37.5%) control mice fed standard Purina chow (440 micro g of selenium/kg) developed PCT by 275 days postpristane. Abrogation of PCT was caused in part by the striking inhibition of the formation of the inflammatory tissue in which PCT develop (pristane granuloma). This was associated with the reduced responsiveness of selenium-deficient inflammatory cells (monocytes and neutrophils) to chemoattractants, such as thioredoxin and chemokines. Selenium-deficient C mice exhibited little evidence of disturbed redox homeostasis and increased mutant frequency of a transgenic lacZ reporter gene in vivo. These findings implicate selenium, via the selenoproteins, in the promotion of inflammation-induced PCT and suggest that small drug inhibitors of selenoproteins might be useful for preventing human cancers linked with chronic inflammations and persistent infections.

Animals↗

PubMed2004

Elevated presence of retrotransposons at sites of DNA double strand break repair in mouse models of metabolic oxidative stress and MYC-induced lymphoma.

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 (lambda-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 lambda-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 lambda-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 approximately 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 lambda-MYC lymphomas and G6PD deficient mice result from the same mechanism, mutagenic repair of DNA double strand breaks arising from oxidative damage.

Animals↗

PubMed2004

Moderate hypermutability of a transgenic lacZ reporter gene in Myc-dependent inflammation-induced plasma cell tumors in mice.

Mutator phenotypes, a common and largely unexplained attribute of human cancer, might be better understood in mouse tumors containing reporter genes for accurate mutation enumeration and analysis. Previous work on peritoneal plasmacytomas (PCTs) in mice suggested that PCTs have a mutator phenotype caused by Myc-deregulating chromosomal translocations and/or phagocyte-induced mutagenesis due to chronic inflammation. To investigate this hypothesis, we generated PCTs that harbored the transgenic shuttle vector, pUR288, with a lacZ reporter gene for the assessment of mutations in vivo. PCTs exhibited a 5.5 times higher mutant frequency in lacZ (40.3 +/- 5.1 x 10(-5)) than in normal B cells (7.36 +/- 0.77 x 10(-5)), demonstrating that the tumors exhibit the phenotype of increased mutability. Studies on lacZ mutant frequency in serially transplanted PCTs and phagocyte-induced lacZ mutations in B cells in vitro indicated that mutant levels in tumors are not determined by exogenous damage inflicted by inflammatory cells. In vitro studies with a newly developed transgenic model of inducible Myc expression (Tet-off/MYC) showed that deregulated Myc sensitizes B cells to chemically induced mutations, but does not cause, on its own, mutations in lacZ. These findings suggested that the hypermutability of PCT is governed mainly by intrinsic features of tumor cells, not by deregulated Myc or chronic inflammation.

Animals↗

PubMed2004

Novel targeted deregulation of c-Myc cooperates with Bcl-X(L) to cause plasma cell neoplasms in mice.

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.

Animals↗

PubMed2003

BCL2 accelerates inflammation-induced BALB/c plasmacytomas and promotes novel tumors with coexisting T(12;15) and T(6;15) translocations.

Previous studies on peritoneal plasmacytomas (PCTs) in BALB/c (C) mice suggested that the enforced expression of the death repressor BCL2 in B cells might facilitate the malignant transformation of aberrant B cells containing Myc-activating T(12;15) translocations, generating an improved model of plasmacytomagenesis. To investigate this hypothesis, we backcrossed a human BCL2 transgene onto strain C and performed a PCT induction study with pristane in the newly generated C.BCL2 congenics. In specific pathogen-free-maintained C.BCL2 mice, PCT incidence (19 of 34, 56%) was 24 times higher than in specific pathogen-free-maintained C mice (1 of 44, 2.3%), and tumor onset (113 days) was half that of conventionally maintained C mice (220 days). BCL2 transgenic PCT harbored T(12;15) translocations (12 of 12 tumors) with an unusual clustering of translocation breakpoints in the near 5' flank of Myc (4 of 5 tumors, 80%). Five tumors contained coexisting T(12;15) and T(6;15) translocations (not observed in >300 karyotyped PCTs from conventionally maintained C mice). BCL2 transgenic C57BL/6 mice exclusively developed B lymphomas (11 of 20, 55%) that also contained T(12;15) translocations (11 of 11 cases) with breakpoints in the near 5' flank of Myc (five of five tumors). We conclude that BCL2 accelerates PCT with novel Myc-activating translocations independently of environmental antigen stimulation. Accelerated plasmacytomagenesis in strain C.BCL2 may be useful for designing and testing BCL2 inhibition strategies in human plasma cell tumors overexpressing BCL2, such as Waldenström's macroglobulinemia and multiple myeloma.

Animals↗

PubMed2003

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.

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 (5.04x10(-5)) and brain (4.55x10(-5)) compared to tissues obtained from normal (Ku+) littermates (7.92x10(-5)and 7.30x10(-5), respectively). No significant difference was found in mutant frequencies in spleen from Ku- (7.21x10(-5)) and Ku+ mice (8.16x10(-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.

Animals↗

PubMed2003

E mu/S mu transposition into Myc is sometimes a precursor for T(12;15) translocation in mouse B cells.

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'-C alpha 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, E mu, and a truncated switch mu region, S mu, were found in the first intron of Myc in lymph node cells of IL-6 transgenic BALB/c mice. In two cases E mu/S mu transposition primed Myc to get involved in apparent trans-chromosomal CSR to C gamma 1, presumably leading to T(12;15). Translocations preceded by E mu/S mu transposition 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 E mu/S mu transposition to Myc may facilitate plasmacytomagenesis by sensitizing Myc to undergo T(12;15) translocation. T(12;15), in turn, juxtaposes Myc to the 3'-C alpha enhancer, which appears to be required for deregulating Myc in a manner that is conducive to PCT development.

Animals↗