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PubMed2002

Malignant myeloid transformation in congenital forms of neutropenia.

BACKGROUND: Granulocyte colony-stimulating factor has had a major impact on the management of severe chronic neutropenia--a collective term referring to congenital, idiopathic, or cyclic neutropenia. Almost all patients respond to G-CSF with increased neutrophils, reduced infections, and improved survival. Some responders with congenital neutropenia (termed Kostmann's syndrome herein) and Shwachman-Diamond syndrome have developed myelodysplastic syndrome and acute myeloid leukemia, which raises the question of the role of G-CSF in pathogenesis. The issue is complicated because both disorders have a propensity for MDS or AML as part of their natural history. OBJECTIVE AND METHODS: To address this, the Severe Chronic Neutropenia International Registry used its large database of chronic neutropenia patients treated with G-CSF to determine the incidence of malignant myeloid transformation in the two disorders, and its relationship to treatment and to other patient characteristics. RESULTS: As of January 2001, of the 383 patients with congenital forms of neutropenia in the Registry, 48 had MDS or AML (crude rate, about 12.5%). No statistically significant relationships were found between age at onset of MDS or AML and patient gender, G-CSF dose, or duration of G-CSF therapy. What was observed, however, was the multistep acquisition of aberrant cellular genetic changes in marrow cells from Kostmann's syndrome patients who transformed, including activating ras oncogene mutations, clonal cytogenetic abnormalities, and G-CSF receptor mutations. The latter in murine models produces a hyperproliferative response to G-CSF, confers resistance to apoptosis, and enhances cell survival. CONCLUSIONS: Since Kostmann's syndrome and Shwachman-Diamond syndrome are inherited forms of bone marrow failure, G-CSF may accelerate the propensity for MDS/AML in the genetically altered stem and progenitor cells, especially in those with G-CSF receptor and ras mutations (82% and 50% of Kostmann's syndrome patients who transform, respectively). Alternatively, and equally plausible, G-CSF may simply be an innocent bystander that corrects neutropenia, prolongs patient survival, and allows time for the malignant predisposition to declare itself. Only careful long-term follow-up of the cohort of patients receiving G-CSF will provide the answer.

Cell Transformation, Neoplastic↗
PubMed1995

Contact-dependent endothelial class II HLA gene activation induced by NK cells is mediated by IFN-gamma-dependent and -independent mechanisms.

NK lymphocytes adhere avidly to allogeneic endothelial cells (ECs) and induce their membrane expression of MHC class II Ags in vitro. Endothelial class II expression augments EC-driven CD4+ T cell proliferation in vitro, and may amplify T cell recruitment and clonal expansion in vivo. Using an ex vivo lymphocyte-skin organ coculture model, NK cells could be found lining and inducing class II HLA on microvessel endothelium. Using neutralizing anti-IFN-gamma and anti-IFN-gamma receptor Abs, a spectrum of IFN-gamma dependence was observed for NK-mediated EC HLA-DR induction at the membrane and transcriptional levels, from negligible to moderate. Trans-well experiments displayed that direct NK-EC contact is required, and Ab inhibition studies indicated that the beta 2 integrin-ICAM-1 pathway(s) is critical in the generation of these responses. The use of HLA-DR alpha promoter constructs in transient transfection assays demonstrated that the highly conserved X and S transcription boxes are required in both IFN-gamma- and NK-mediated gene activation. As expected, because of the receptor species specificity, human IFN-gamma did not induce HLA-DR alpha promoter constructs transfected in Chinese hamster ovary cells, whereas NK cells did. Taken together, these results indicate that human allogeneic NK lymphocytes induce EC class II HLA gene activation and membrane expression in an adhesion-dependent, IFN-gamma-independent fashion and suggest that, in concert with any IFN-gamma-dependent component, this induction could represent an efficient mode of endothelial activation and immune amplification in vivo.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1995

Gene deletion explains both in vivo and in vitro generated chromosome 2 aberrations associated with murine myeloid leukemia.

Ninety-five percent of radiation-induced murine myeloid leukemias contain chromosome 2 aberrations. A dominant molecular defect has not yet been identified: both deletions and breakpoint-specific events have been postulated. We have generated a model in which chromosome 2 lesions have been generated in vitro in a clonal tumor cell line. In this study cytogenetic and molecular comparisons are made between two of these in vitro generated lesions and eight derived in vivo: seven by the conventional radiation protocol, and one by infection with Moloney leukemia virus. All 10 lines consistently exhibited hemizygous loss of an 18 cM region between Hoxd-4 and II-1 alpha, with variable breakpoints at both ends. These results are consistent with deletion of a gene in common rather than breakpoint-specific events, for lesions resulting from all three protocols. This will allow a novel approach to the identification of a putative tumor suppressor gene, ie to describe the biological effect of the in vitro generated deletion, and to clone the gene by complementation. In preparation for this approach, we have further narrowed the region to approximately 6.5 cM by microsatellite mapping of 22 radiation-induced F1 tumors. In addition, we have eliminated the possibility that imprinting ablates expression from the remaining undeleted chromosome.

Animals↗
PubMed1997

[Detection of antigen specific T cell clonality in autoimmune diseases and epitope analysis of autoantigen-reactive T cells].

In order to develop an ultimate therapy to overcome autoimmune diseases, it is very important to identify whether or not autoantigen-reactive T cells accumulate in such diseases. A novel method was established to analyze T cell clonality using a combination of reverse transcriptase-polymerase chain reaction of T cell receptor beta chain transcripts and single-strand conformation polymorphism (RT-PCR/SSCP). Using RT-PCR/SSCP, clonal expansion of T cells were identified in NOD mouse, collagen induced arthritis model, rheumatoid arthritis, Crohn's disease, Sjögren's syndrome, bone marrow transplantation, pregnancy, malignant tumors, HTLV-I associated myopathy, and interstitial pneumonia. By using a tandem mass spectrometry or a lymphocytic proliferation assay, T cell epitopes were mapped in NOD mice, EAE, MCTD, and melanoma.

Animals↗
PubMed1994

[Viral antigen induced autoimmunity: an animal model for diabetes mellitus type I].

To address the mechanisms of tolerance to extrathymic proteins, we have generated transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) in the beta islet cells of the pancreas. The fate of LCMV-GP-specific T cells was followed by breeding the GP transgenic mice with T cell receptor transgenic mice, specific for LCMV-GP and H-2Db. These studies suggest that "Peripheral tolerance" of self-reactive T cells does not involve clonal deletion, clonal anergy, or a decrease in the density of T cell receptors or accessory molecules. Instead, this model indicates that potentially self-reactive cytotoxic T cells may remain functionally unresponsive, owing to a lack of appropriate T cell activation. Infection of transgenic mice with LCMV readily abolishes peripheral unresponsiveness to the self LCMV-GP antigen, resulting in a CD8+ T cell-mediated diabetes. These data suggest that similar mechanisms may operate in several so called "T cell-mediated autoimmune diseases". A synthetic peptide corresponding to an immunodominant epitope of lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) was used to prime or to tolerize CD8+ T cells in vivo, dependent on the mode of immunization. Peptide-specific tolerance was then examined in transgenic mice expressing LCMV-GP in the beta islet cells of the pancreas; these mice develop CD8+ T cell-mediated diabetes within 8-14 days after LCMV infection. Specific peptide-induced tolerance prevented autoimmune destruction of beta islet cells and diabetes in this transgenic mouse model.

Animals↗
PubMed2002

Loss of heterozygosity analysis of cutaneous melanoma and benign melanocytic nevi: laser capture microdissection demonstrates clonal genetic changes in acquired nevocellular nevi.

The molecular pathology of the common nevocellular nevus (NCN) and its relationship to the genetic model of malignant melanoma (MM) progression has not been fully characterized. We used laser capture microdissection of archival formalin-fixed material to study 34 melanocytic lesions (19 MM and 15 NCN). Twelve of the 15 NCN were acquired, 3 of which were congenital; none had dysplastic features. Ten polymorphic markers on five chromosomal regions (1p36, 6q22-23.3, 8p22-24, 10q23, and 11q23) were selected for loss of heterozygosity (LOH) analysis, based on previous studies demonstrating involvement in MM pathogenesis and progression. Loss of heterozygosity at any allelic locus was observed in 18 of 19 (95%) MM and in 9 of 15 (60%) NCN. Of the three congenital nevi analyzed, none showed LOH at any informative locus. The frequency of allelic loss was highest in the MM at 6q22-23.3 (64%), followed by 10q23 (62%), 8p22-24 (43%), 11q23 (43%), and 1p36 (13%). In the 15 NCN, the most frequent allelic losses were detected at 6q22-23.3 (29%), 1p36 (27%), and 10q23 (25%), with lower frequencies of LOH at 11q23 (10%) and 8p22-24 (7%). LOH at a single polymorphic marker, D6S1038, was detected in 70% of the MM and in 36% of the NCN, suggesting the presence of putative tumor-suppressor genes (TSGs) critical in melanocytic neoplasia at 6q22-23.3. The presence of clonal genetic alterations in acquired NCN justifies their classification as a benign neoplasm. The pattern of LOH in NCN is not random; rather, the relative frequencies of LOH at the chromosomal regions examined are consistent with a multistep model of MM progression that begins with NCN. Molecular analysis of NCN reiterates established epidemiologic and morphologic notions that NCN are precursor lesions for MM.

Adult↗
PubMed1998

Liver repopulation with xenogenic hepatocytes in B and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of hepatocellular carcinoma.

To investigate host and viral mechanisms determining hepadnaviral persistence and hepatocarcinogenesis, we developed a mouse model by transplanting woodchuck hepatocytes into the liver of mice that contain the urokinase-type plasminogen activator transgene (uPA) and lack mature B and T lymphocytes due to a recombination activation gene 2 (RAG-2) gene knockout. The woodchuck hepatocytes were transplanted via intrasplenic injection and were found to integrate into the recipient mouse liver cord structure. Normal adult woodchuck hepatocytes proliferated and reconstituted up to 90% of the uPA/RAG-2 mouse liver. uPA/RAG-2 mice containing woodchuck hepatocytes were infectable with woodchuck hepatitis virus (WHV) and showed WHV replication for at least 10 months with titers up to 1 x 10(11) virions per ml in the peripheral blood. WHV-infected hepatocytes from chronic carrier woodchucks also established a persistent infection in uPA/RAG-2 mice after an 8- to 12-week lag period of viremia. Although WHV envelope, core, and X proteins were produced in the uPA/RAG-2 mice, no inflammatory host immune response was observed in the liver of WHV-replicating mice. A first antiviral test demonstrated a greater than four orders of magnitude drop in WHV titer in response to interferon alpha treatment. WHV replication was up-regulated by dexamethasone treatment. Comparison of precancerous lesions in donor woodchucks versus recipient uPA/RAG-2 mice revealed an enrichment of dysplastic precancerous hepatocytes in transplanted mice. Clonal amplification of hepatocytes from a woodchuck with hepatocellular carcinomas was demonstrated by the detection of unique WHV DNA integration patterns in hepatocellular carcinomas that arose in uPA/RAG-2 mice. In the absence of B or T cell-mediated immune responses, WHV establishes a persistent noncytotoxic infection of woodchuck hepatocytes in uPA/RAG-2 chimeric mouse livers. Further studies of the kinetics of hepadnavirus infection and replication in quiescent and proliferating hepatocytes should increase our understanding of hepadnavirus spread and aid in the design of therapies to block or cure persistent infection.

Animals↗
PubMed1990

Relationships between sequestration, antigenic variation and chronic parasitism in Plasmodium chabaudi chabaudi--a rodent malaria model.

We describe here a rodent malaria model using cloned lines of Plasmodium chabaudi chabaudi in inbred CBA/Ca mice that exhibits both clonal antigenic variation in late stage-specific surface antigens, and deep vascular schizogony in the liver. We show that both these features are modulated by the spleen, and that surface antigen expression is crucially involved in the sequestering phenotype. Surface antigens are variant in chronic infection, and host protective immune responses can distinguish between these variants. Splenectomy abolishes this difference. The acute infection with non-sequestering cloned lines is kinetically indistinguishable from sequestering clones, but parasites unable to express variant sequestration-associated antigen do not form a chronic recrudescing infection. Another clone, able to re-express this antigen in the presence of the spleen, undergoes typical chronic recrudescence. In this model, the biological significance of sequestration-associated variant antigen seems to enable the establishment of chronic infection in the presence of a primed spleen.

Animals↗
PubMed2004

In a transgenic model of spontaneous autoimmune diabetes, expression of a protective class II MHC molecule results in thymic deletion of diabetogenic CD8+ T cells.

H-2(d) mice expressing both the influenza virus hemagglutinin (HA) as a transgene-encoded protein on pancreatic islet beta cells (InsHA), as well as the Clone 4 TCR specific for the dominant H-2K(d)-restricted HA epitope, can be protected from the development of spontaneous autoimmune diabetes by expression of the H-2(b) haplotype. Protection occurs due to the deletion of K(d)HA-specific CD8+ T cells. This was unexpected as neither the presence of the InsHA transgene nor H-2(b), individually, resulted in thymic deletion. Further analyses revealed that thymic deletion required both a hybrid MHC class II molecule, Ebeta(b) Ealpha(d), and the K(d) molecule presenting the HA epitope, which together synergize to effect deletion of CD4+CD8+ thymocytes. This surprising example of protection from autoimmunity that maps to a class II MHC molecule, yet effects an alteration in the CD8+ T cell repertoire, suggests that selective events in the thymus represent the integrated strength of signal delivered to each cell through recognition of a variety of different MHC-peptide ligands.

Animals↗
PubMed1992

The NZB mouse as a model for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and the only leukemia for which a possible genetic component has been described. Analysis of this genetic component has been hindered by the fact that disease onset normally occurs after age 50. We report here the aged NZB mouse as an animal model for CLL. NZB mice have a genetically regulated, age-dependent onset of clonal, aneuploid cells which are IgM+ and Ly1+ (CD5+ B-cells). Peripheral blood smears from old NZB mice show an increase in circulating lymphocytes and "smudged" or ruptured cells, often seen in human CLL. Electron microscopic examination of these cells shows them to be mature lymphocytes. Light microscopy of the spleen shows infiltration of small lymphocytes and is consistent with CLL pathology. These long-lived, CLL-like cells can be serially passaged into recipient animals. This continued passage occasionally results in the development of a large cell lymphoma detectable in the spleen, lymph nodes, and liver. The histology of this lymphoma is quite distinct from that of the CLL-like cells, but the phenotype is that of an aneuploid CD5+, IgM+ cells. This apparently represents a continued transformation of the CLL-like clone similar to the development of Richter's syndrome in human CLL. Therefore, the NZB mouse can be a valuable tool for the determination of the genetic basis of CLL ontogeny and the conversion of CLL into Richter's syndrome.

Age Factors↗
PubMed1989

Is the gene for von Recklinghausen neurofibromatosis somatically unstable?

The yellow-nonyellow pattern of the tortoiseshell guinea pig is presented as a model for the distribution of mutant and nonmutant neural-crest cells in von Recklinghausen neurofibromatosis (NF-1). The following hypotheses are offered to explain the developmental genetics of the variable phenotype. (1) The gene for NF-1 is somatically unstable; reverse somatic mutation occurs at a high frequency among the stem cells of clones of neural-crest cells in all affected individuals. (2) The normal reverted cells suppress the proliferation of residual mutant cells when both types are in close proximity. (3) At puberty, proliferation of normal cells decelerates, but proliferation in islands of residual mutant cells accelerates and results in the development of neurofibromas. (4) Plexiform neurofibromas occur when reverse mutation fails to occur or takes place relatively late within a large clonal population of mutant cells.

Animals↗
PubMed1996

Long-term survival of solid organ allografts by brief anti-lymphocyte function-associated antigen-1 monoclonal antibody monotherapy.

Strategies targeting lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18) and intercellular adhesion molecule-1 (ICAM-1) have previously been shown to produce long-term survival of solid organ allografts in animals only when both CD11a and ICAM-1 are targeted for a brief (6-7 days) time or when extended (14 weeks) treatment with anti-CD11a monoclonal antibody (mAb) is administered. We show that recipient pretreatment followed by a brief (13 days) treatment course with high-dose anti-CD11a mAb alone produces long-term survival of cardiac allografts in the rigorous, nonprimarily vascularized heart allograft model in mice. This treatment regimen induces specific unresponsiveness in our model. In recipients bearing long-term beating cardiac grafts after treatment with anti-CD11a mAb, there still exists a high frequency of potentially antigen-reactive T cells in isolated peripheral blood lymphocyte fractions. Therefore, clonal deletion does not appear to explain the induction of specific unresponsiveness by treatment with anti-CD11a mAb in this model. These findings support the further investigation of the use of high-dose anti-LFA-1 mAb monotherapy in the pre- and early postoperative period to promote solid organ allograft survival.

Animals↗
PubMed2005

Telomere length and telomerase activity in the BCR-ABL-transformed murine Pro-B cell line BaF3 is unaffected by treatment with imatinib.

OBJECTIVE: Imatinib mesylate is a novel tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome positive (Ph+) leukemia and other malignancies. In previous studies, we found significant telomere shortening in Ph+ cells from patients with chronic myeloid leukemia (CML). Interestingly, imatinib treatment was found to lead to a normalization of previously shortened telomere length in CML patients. Based on recent reports demonstrating that c-ABL phosphorylates hTERT and thereby inhibits hTERT activity, a direct effect of imatinib on hTERT activity leading to telomere elongation in BCR-ABL-positive cells has been proposed by others. Such an effect could be of potential importance for telomere maintenance in Ph+ cells by facilitating clonal selection and progression of the disease to blast crisis. METHODS: We investigated the impact of imatinib on telomere length and telomerase activity of the interleukin-3 (IL-3)-dependent murine pro-B cell line BaF3 and the BCR-ABL-positive, IL-3-independent transfectant BaF3p185 in vitro. RESULTS: When BaF3 and BaF3p185 cells were treated with imatinib (the latter being rescued with IL-3), no effect on either telomerase activity or telomere length was observed. These findings can be explained by the cytoplasmatic localization of BCR-ABL found in BaF3p185 as compared to the nuclear localization of telomerase (and c-ABL). CONCLUSION: As opposed to recent reports for c-ABL, we do not see evidence for a functional interaction between BCR-ABL and hTERT in this model system arguing against imatinib-mediated upregulation of hTERT as a crucial factor for clonal selection and disease progression of CML.

Animals↗
PubMed2006

Development and function of naturally occurring CD4+CD25+ regulatory T cells.

The immune system has evolved numerous mechanisms of peripheral T cell immunoregulation, including a network of regulatory T (Treg) cells, to modulate and down-regulate immune responses at various times and locations and in various inflammatory circumstances. Amongst these, naturally occurring CD4(+)CD25(+) Treg cells (nTreg) represent a major lymphocyte population engaged in the dominant control of self-reactive T responses and maintaining tolerance in several models of autoimmunity. CD4(+)CD25(+) Treg cells differentiate in the normal thymus as a functionally distinct subpopulation of T cells bearing a broad T cell receptor repertoire, endowing these cells with the capacity to recognize a wide range of self and nonself antigen specificities. The generation of CD4(+)CD25(+) Treg cells in the immune system is genetically controlled, influenced by antigen recognition, and various signals, in particular, cytokines such as interleukin-2 and transforming growth factor-beta1, control their activation, expansion, and suppressive effector activity. Functional abrogation of these cells in vivo or genetic defects that affect their development or function unequivocally promote the development of autoimmune and other inflammatory diseases in animals and humans. Recent progress has shed light on our understanding of the cellular and molecular basis of CD4(+)CD25(+) Treg cell-mediated immune regulation. This article discusses the relative contribution of CD4(+)CD25(+) nTreg cells in the induction of immunologic self-tolerance and provides a comprehensive overview of recent finding regarding the functional properties and effector mechanism of these cells, as revealed from various in vitro and in vivo models.

Animals↗
PubMed2006

Caspase-3 induced apoptosis in transgenic zebrafish.

Zebrafish is an attractive model organism for studying apoptosis development because of its genetic accessibility. Here we describe the induction of clonally derived apoptosis in transgenic zebrafish expressing mouse caspase-3 (CASP3) under control of the zebrafish beta-actin promoter (betap). Visualization of apoptotic cells, expressing a chimeric transgene encoding CASP3 fused to green fluorescent protein (GFP) gene, revealed that apoptosis arose in the thymus, spread locally into gill arches and retro-orbital soft tissue, and then disseminated into abdominal organs like testis, kidney. This transgenic model provides a platform for over-expression of caspase-3 induced extensive apoptosis in embryos and adult.

Actins↗
PubMed2026

Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.

Glioblastoma (GBM) is one of the most aggressive and lethal primary brain tumors in adults, characterized by dynamic clonal evolution and extensive genomic, cellular, spatial, and microenvironmental heterogeneity. Multi-omics studies have revealed that GBM follows complex evolutionary trajectories involving genetic, epigenetic, transcriptional, and immune-microenvironmental remodeling as tumors grow, adapt to the brain microenvironment, and acquire therapeutic resistance. Increasing evidence suggests that GBM may originate from aberrant neural stem or progenitor cells, including those residing in the subventricular zone, and that glioblastoma stem cells (GSCs) contribute to tumor propagation, heterogeneity, and recurrence. A key conceptual challenge is to reconcile hierarchical cancer stem cell models, in which GSCs are viewed as relatively stable tumor-propagating subpopulations, with dynamic state plasticity models, in which stem-like properties can be reversibly acquired or lost during transitions among proneural-like, mesenchymal-like, invasive, and therapy-tolerant states. Recent advances in single-cell profiling, spatial transcriptomics, lineage tracing, organoid culture, 3D bioprinting, genetically engineered models, and artificial intelligence (AI)-assisted computational modeling have substantially improved the ability to study these processes. However, no currently available model fully recapitulates human GBM heterogeneity, recurrence, treatment history, and tumor-microenvironment interactions. Therefore, model selection should be guided by clearly defined mechanistic questions rather than by reliance on any single platform. This review summarizes current advances in in vitro, ex vivo, in vivo, and computational models for studying GBM evolution and heterogeneity, and discusses how integrated model pipelines may improve preclinical drug testing, treatment-response prediction, and precision neuro-oncology.

Humans↗
PubMed2006

On the origin of syn- and metachronous urothelial carcinomas.

OBJECTIVE: To evaluate existing models for the origin of meta- and synchronous urothelial carcinomas in light of the accumulated genetic data. METHODS: Published studies on the clonal origin and genetic relationships of syn- and metachronous tumors, genetic aberrations in normal and premalignant urothelial lesions, as well as histologic and genetic mapping studies of cystectomized bladder samples are reviewed. RESULTS: The most common models for the origin of syn- and metachronous tumors are found to conform less well to the accumulated genetic data. A new model is proposed, the field-first-tumor-later model, in which aberrant cells with a stem cell, or stem cell-like, origin spread in the urothelium by cellular displacement, creating fields of premalignant cells. Tumor growth is suggested to be initiated by critical genetic events occurring in individual cells in such fields. Hence, recurring tumors are proposed to originate from a shared field of premalignant cells and not from previous overt tumors. CONCLUSIONS: The proposed model can better account for the existing genetic and histological data on syn- and metachronous urothelial carcinomas.

Humans↗