Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bcr/abl chimeric oncoprotein is considered to be implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias. To investigate its biological function and the role in leukemogenesis in vivo, we generated transgenic mice expressing p210bcr/abl driven by the metallothionein promoter. Two of six founder mice and the transgenic progeny of one leukemic founder mouse developed leukemias several months after birth. Phenotypically, each leukemic mouse showed a thymic enlargement, a marked splenomegaly, and/or lymphnode swellings. Pathological examination revealed that leukemic cells were infiltrated in all tissues examined, especially in thymus, spleen, liver, and lymphnode. Expression of the p210bcr/abl transgene product and increased phosphorylation of cellular proteins in leukemic tissues were detected by the Western blot analysis. In addition, the expressed p210bcr/abl protein was demonstrated to possess an enhanced kinase activity by the in vitro immunecomplex kinase assay. These results indicate that hematopoietic precursor cells expressing the p210bcr/abl transgene product acquired a proliferative advantage and eventually developed leukemias in transgenic mice. The p210bcr/abl transgenic mice are considered to be an excellent animal model to investigate p210bcr/abl function and its role in leukemogenesis in vivo.
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PMID:[An animal model of leukemogenesis using transgenic mice]. 764 51

The effects of tamoxifen (TAM), its 3-hydroxy congener droloxifene (DROL) and 17 beta-estradiol were investigated on leukemogenesis induced in BALB/c mice by Rauscher murine leukemia virus (RLV). Multiple applications of each compound, in a dose-dependent manner, resulted in reduced virus titer in the serum, delayed onset of splenomegaly and significant prolongation of survival. Although 17 beta-estradiol proved most effective, prevention of disease was not achieved either by short- or long-term treatment with any of the drugs tested.
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PMID:Effects of tamoxifen, droloxifene and 17 beta-estradiol on Rauscher mouse leukemogenesis. 803 74

The candidate proto-oncogene BCL3 was isolated through its involvement in the t(14;19) found in chronic lymphocytic leukemia and other B-cell neoplasms. As a member of the I kappaB family, BCL3 plays a role in the immune response by interactions with the NF-kappaB family of transcription factors. In order to study the role of BCL3 overexpression in lymphoid malignancies, we generated five lines of E mu-BCL3 transgenic mice. Transgenic animals develop normally but show splenomegaly and an accumulation of mature B cells in lymph nodes, bone marrow and peritoneal cavity. A hyperresponsive immune system is suggested by the follicular hyperplasia and plasmacytosis in lymph nodes of unimmunized animals, increased incidence of antibodies to self-antigens, and a heightened response to cross-linking of surface IgM. Statistically significant decreases in serum IgM and IgG3, but an increase in IgG1 and IgA were also observed. No lymphoid neoplasms have been identified in transgenic animals. The expansion of B cells in vivo is consistent with the overexpression of BCL3 as being one step in the multi-step process of leukemogenesis. The phenotype also suggests that BCL3 plays a part in B cell proliferation and isotype switching.
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PMID:Lymphadenopathy, splenomegaly, and altered immunoglobulin production in BCL3 transgenic mice. 962 May 50

Polycythemia vera (PV), one of the chronic myeloproliferative disorders (MPD), is characterized by predominant erythroid proliferation and secondary platelet proliferation, and by progression from a proliferative stage to a metastatic phase and finally a malignant phase. These characteristics expose patients to increased risk for thrombohemorrhagic complications, myeloid metaplasia, myelofibrosis, and acute leukemic conversion irrespective of treatments. Currently, there are three agents-hydroxyurea (HU), interferon-alfa (IFN-alpha), and anagrelide-that differ in mechanisms of action and in treating specific phenotypic manifestations of PV, suggesting a potential role for combination therapy. They also differ widely in side effects profiles and severity. Because of the differing risks for long-term complications associated with these agents, age is an important variable in selecting treatments. Patients at high risk for thrombohemorrhagic complications all require cytoreduction, as do patients at intermediate risk who are not effectively managed by phlebotomy and low-dose aspirin. In younger patients, the safest and most effective combination treatment appears to be anagrelide plus IFN-alpha, while in older patients anagrelide plus hydroxyurea may be effective. HU is used sparingly in younger patients because of the long-term increased risk of mutagenicity and possibly leukemogenesis. IFN-alpha is particularly indicated for patients with myeloid metaplasia evidenced by splenomegaly. Anagrelide, which acts on the mature megakaryocyte to prevent platelet budding, is uniquely efficacious in the control of platelet counts.
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PMID:Modern treatment strategies in polycythemia vera. 1268 79

Of the current mouse chronic myelogenous leukemia (CML) models,the murine bone marrow (BM) transduction and transplantation model most efficiently mimics many of the central features of human CML. In this model, lethally irradiated mice are reconstituted with primary murine BM cells transduced with a P210BCR/ABL retrovirus. All recipient mice develop a fatal peripheral blood and BM granulocytosis and splenomegaly, a disease termed the murine CML-like myeloproliferative disorder. This model has been used to establish the causative role of Bcr/Abl in CML, identify those signaling pathways and regions of Bcr/Abl critical for leukemogenesis, and explore the limitations of targeted CML therapy. Future refinements in this CML mouse model will make it a more effective tool for studying imatinib-resistant CML, reproducing chronic- and blastic-phase human CML, and performing CML progenitor studies.
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PMID:Animal models of chronic myelogenous leukemia. 1527 91

To develop murine models of leukemogenesis, a series of transgenic mice expressing BCR-ABL in different hematopoietic cell subsets was generated. Here we describe targeted expression of P210 BCR-ABL in stem and progenitor cells of murine bone marrow using the tet-off system. The transactivator protein tTA was placed under the control of the murine stem cell leukemia (SCL) gene 3' enhancer. Induction of BCR-ABL resulted in neutrophilia and leukocytosis, and the mice became moribund within 29 to 122 days. Autopsy of sick mice demonstrated splenomegaly, myeloid bone marrow hyperplasia, and extramedullary myeloid cell infiltration of multiple organs. BCR-ABL mRNA and protein were detectable in the affected organs. Fluorescence-activated cell sorter (FACS) analysis demonstrated a significant increase in mature and immature myeloid cells in bone marrow and spleen, together with increased bilineal B220+/Mac-1+ cells in the bone marrow. tTA mRNA was expressed in FACS-sorted hematopoietic stem cells expanded 26-fold after BCR-ABL induction. Thirty-one percent of the animals demonstrated a biphasic phenotype, consisting of neutrophilia and subsequent B-cell lymphoblastic disease, reminiscent of blast crisis. In summary, this mouse model recapitulates many characteristics of human chronic myeloid leukemia (CML) and may help elucidate basic leukemogenic mechanisms in CML stem cells during disease initiation and progression.
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PMID:Inducible chronic phase of myeloid leukemia with expansion of hematopoietic stem cells in a transgenic model of BCR-ABL leukemogenesis. 1533 42

AML1 (RUNX1) encodes a DNA-binding subunit of the CBF transcription factor family and is required for the establishment of definitive hematopoiesis. AML1 is one of the most frequently mutated genes associated with human acute leukemia, suggesting that genetic alterations of the gene contribute to leukemogenesis. Here, we report the analysis of mice carrying conditional AML1 knockout alleles that were inactivated using the Cre/loxP system. AML1 was deleted in adult mice by inducing Cre activity to replicate AML1 deletions found in human MDS, familial platelet disorder and rare de novo human AML. At a latency of 2 months after induction, the thymus was reduced in size and frequently populated by immature double negative thymocytes, indicating defective T-lymphocyte maturation, resulting in lymphatic diseases with 50% penetrance, including atypical hyperplasia and thymic lymphoma. Metastatic lymphomas to the liver and the meninges were observed. Mice also developed splenomegaly with an expansion of the myeloid compartment. Increased Howell-Jolly body counts indicated splenic hypofunction. Thrombocytopenia occurred due to immaturity of mini-megakaryocytes in the bone marrow. Together with mild lymphocytopenia in the peripheral blood and increased fractions of immature cells in the bone marrow, AML1 deficient mice display features of a myelodysplastic syndrome, suggesting a preleukemic state.
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PMID:AML1 deletion in adult mice causes splenomegaly and lymphomas. 1624 65

In 1871, the observation of yellowish nodules in the enlarged spleen of a cow was considered to be the first reported case of bovine leukemia. The etiological agent of this lymphoproliferative disease, bovine leukemia virus (BLV), belongs to the deltaretrovirus genus which also includes the related human T-lymphotropic virus type 1 (HTLV-1). This review summarizes current knowledge of this viral system, which is important as a model for leukemogenesis. Recently, the BLV model has also cast light onto novel prospects for therapies of HTLV induced diseases, for which no satisfactory treatment exists so far.
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PMID:Mechanisms of leukemogenesis induced by bovine leukemia virus: prospects for novel anti-retroviral therapies in human. 1736 24

SET-CAN associated with the t(9;9) in acute undifferentiated leukemia encodes almost the entire sequence of SET and the C-terminal two-third portion of CAN, including the FG repeat region. To clarify a role(s) of SET-CAN in leukemogenesis, we developed transgenic mice expressing SET-CAN under the control of the Gata1 gene hematopoietic regulatory domain that is active in distinct sets of hematopoietic cells. SET-CAN transgenic mice showed anemia, thrombocytopenia, and splenomegaly. A significant number of transgenic mice started dying after 6 months post-birth, being in good agreement with the fact that red blood cells and platelets decreased. We found that a significant number of c-kit+ myeloid cells appeared in peripheral blood in transgenic mice. Characterization of the bone marrow cells of transgenic mice indicated impairment in hematopoietic differentiation of erythroid, megakaryocytic, and B cell lineages by SET-CAN. Transgenic mice, in particular, exhibited a high population of the c-kit+Sca-1+Lin- fraction in bone marrow cells compared with that of the control littermates. Our results demonstrate that SET-CAN blocks the hematopoietic differentiation program--one of the characteristics of acute myeloid leukemia.
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PMID:Impairment of erythroid and megakaryocytic differentiation by a leukemia-associated and t(9;9)-derived fusion gene product, SET/TAF-Ibeta-CAN/Nup214. 1762 Mar 17

To investigate the pathogenic risk of endogenous retroviruses (ERVs) infection in immunodeficient hosts, the ERV of N-type ecotropic murine leukemia virus (MuLV) isolated from SL mice, a kind of mice containing considerable infectious ERV particles determined with SC-XC test and developing leukemia spontaneously with average of high frequency of 30% and incubation period of 315days, was inoculated intraperitoneally into newborn CBA nude mice. The distinct marker of splenomegaly for leukemia was observed in 33% of homozygous (nu/nu) and 17% of heterozygous (nu/+) of CBA nude mice with average incubation period of 310days and 432days post-inoculation, respectively. Furthermore, the ERV induced leukemia in both the SL mice and CBA nude mice was identified to be B lymphatic, transplantable and with rearrangement of the Evi-1 locus. The higher induction of leukemia and rearrangement of the Evi-1 locus in CBA nude mice are considered to be dependent on the lower immune status of the hosts. These findings indicate that the ERV could present the host immune dependent leukemogenesis in immunodeficient hosts through the Evi-1 gene rearrangement and suggest that screening of ERVs may be necessary in clinical transplantation or transfusion.
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PMID:Pathogenic risk of endogenous retrovirus infection in immunodeficient hosts. 1817 81


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