RESUMO
BACKGROUND: Infant leukemias have a high frequency of mixed lineage leukemia (MLL) gene rearrangements. PROCEDURE: Using data from a large etiologic study, we evaluated the distribution of selected demographic factors among 374 infant leukemia cases by leukemic subtype, MLL status and diagnosis age. RESULTS: Overall, 228 cases were MLL+. Compared to white infants, black infants were significantly less likely to have MLL+ leukemia. Further, there was a statistically significantly higher age at diagnosis for infants with t(9;11) translocations compared to all other translocation partners in both acute lymphoblastic leukemia and acute myeloid leukemia cases. CONCLUSION: These patterns may provide important etiological insight into the biology of infant leukemia.
Assuntos
Leucemia/epidemiologia , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Distribuição por Idade , Idade de Início , Feminino , Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Distribuição por SexoRESUMO
Neural progenitor cells (NPCs) have shown ability to repair injured CNS, and might provide precursors to retinal neurons. NPCs were isolated from the brains of 14 day murine embryos of transgenic mice that express beta-galactosidase (beta-gal) on the arrestin promoter, which specifically directs expression to retinal photoreceptor cells. NPCs were transferred to adult, syngeneic mice via inoculation into the anterior chamber of the eye, the peritoneal cavity, or the brain. At 14 weeks postgrafting, tissues were collected and examined to determine if differentiated NPC progeny were present in retina based on histochemical detection of beta-gal. Four of six anterior chamber-inoculated recipients showed Bluo-gal-stained cells in retina, indicating the presence of transferred NPCs or their progeny. Because the progenitor cells do not express beta-gal, positive staining indicates differentiation leading to activation of the arrestin promoter. Two recipients inoculated by the intraperitoneal route also exhibited Bluo-gal staining in retina. The NPCs did not express beta-gal if inoculated into brain, but survived and dispersed. Most recipients, regardless of inoculation route, were PCR positive for beta-gal DNA in extraocular tissues, but no Bluo-gal staining was found outside of the retina. Injury to the retina promoted, but was not required, for progenitor cell engraftment. beta-Gal-positive cells were concentrated in the outer layers of the retina. In summary, a reporter gene specifically expressed in differentiated retinal photoreceptor cells due to the activity of the arrestin promoter was expressed in recipient mouse retina following transfer of NPCs prepared from the beta-gal transgenic mice. The presence of beta-gal DNA, but not Bluo-gal staining, in spleen and other tissues revealed that the cells also migrated elsewhere and took up residence in other organs, but did not undergo differentiation that led to beta-gal expression.
Assuntos
Diferenciação Celular/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Neurônios/citologia , Células Fotorreceptoras/citologia , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Animais , Arrestina/genética , Encéfalo/citologia , Química Encefálica , Diferenciação Celular/fisiologia , Movimento Celular , DNA/análise , Imunofluorescência , Regulação da Expressão Gênica , Histocitoquímica , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Cavidade Peritoneal/citologia , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Retina/química , Retina/citologia , Doenças Retinianas/terapia , Baço/química , Baço/citologia , Células-Tronco/fisiologia , beta-Galactosidase/genéticaRESUMO
The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin(-)Sca1(+)c-kit(+)) stem cells, while committed granulocyte-monocyte progenitors (GMPs) were transformation resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll-AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 upregulated expression of 192 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors.
Assuntos
Transformação Celular Neoplásica , Regulação Neoplásica da Expressão Gênica , Leucemia/genética , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Animais , Divisão Celular , Dosagem de Genes , Células-Tronco Hematopoéticas/citologia , Humanos , Cinética , Camundongos , Camundongos Transgênicos , Retroviridae/genética , Células-Tronco/citologiaRESUMO
Although several observations show local T cell recognition of retinal Ag, there has been no direct demonstration that the APC were retinal derived, rather than recruited. In this study, CD45(+) cells isolated from immunologically quiescent murine retina were tested in vitro for functional evidence of Ag presentation to naive and Ag-experienced CD4 T cells specific for beta-galactosidase. Because CD45(+) cells from brain have been reported to be efficient APC, they were included for comparison. Measures of activation included changes in CD4, CD25, CD44, CD45RB, CD62L, CD69, caspase-3 activation, CFSE dilution, size, number of cells recovered, and cytokine production. Retinal CD45(+) cells gave no evidence of Ag-dependent TCR ligation in naive T cells, unlike splenic APC and CD45(+) cells from brain, which supported potent responses. Instead, addition of retinal CD45(+) cells to cocultures of naive 3E9 T cells plus splenic APC reduced the yield of activated T cells and cytokine production by limiting T cell activation at early time points. Ag-experienced T cells responded weakly to Ag presented by retinal CD45(+) cells. Activating the retinal cells with IFN-gamma, anti-CD40, or LPS incrementally increased their APC activity. Addition of neutralizing Abs to TGF-beta did not reveal suppressed retinal APC activity. Because retina lacks tissue equivalents of meninges and choroid plexus, rich sources of dendritic cells in brain, cells from retina may better represent the APC activity of fresh, adult CNS parenchymal and perivascular cells. The activity of the retinal CD45(+) cells appears to be directed to limiting T cell responses.
Assuntos
Apresentação de Antígeno , Antígenos Comuns de Leucócito/análise , Microglia/imunologia , Retina/imunologia , Animais , Células Dendríticas/fisiologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Linfócitos T/imunologiaRESUMO
Borrelia burgdorferi sensu stricto (s.s.), the causative agent of Lyme disease in North America is transmitted to the mammalian host by ticks belonging to the genus, Ixodes. Antibodies to several spirochetal proteins, most notably outer surface protein C (OspC), have been observed in early infection in both humans and laboratory animals. Thus, the expression of these proteins have been postulated to play a role in tick transmission and spirochetal infectivity for the mammalian host. B. burgdorferi strain JMNT was induced to produce increased levels of OspC by cultivation in BSK medium at 37 degrees C. To diminish expression of OspC, spirochetes were cultivated at 31 degrees C. Spirochetes shifted down from 37 degrees C to 31 degrees C or up from 31 degrees C to 37 degrees C for 1 week contained equivalent amounts of OspC. To evaluate spirochetal infectivity, hamsters were inoculated subcutaneously with 1 x 10(4) or 1 x 10(6) spirochetes grown at the above-mentioned temperatures. Hamsters inoculated with spirochetes expressing high amounts of OspC all became infected, irrespective of the inoculum size. None of the hamsters inoculated with 1 x 10(4) spirochetes grown at 31 degrees C or in cultures shifted down from 37 degrees C to 31 degrees C were infected. All infected hamsters, confirmed by isolation of spirochetes in ear and/or bladder cultures, had an antibody response to OspC. In contrast, all non-infected hamsters lacked antibodies to OspC. We conclude that cultivation of spirochetes at 37 degrees C enhances their infectivity for hamsters. This study also suggests there is a correlation between enhancement of OspC expression and spirochetal infectivity for hamsters.