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  1 / 3793 MEDLINE  
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PMID:28210005
Autor:Shima Y; Yumoto M; Katsumoto T; Kitabayashi I
Dirección:Division of Hematological Malignancy, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Título:MLL is essential for NUP98-HOXA9-induced leukemia.
Fuente:Leukemia; 31(10):2200-2210, 2017 Oct.
ISSN:1476-5551
País de publicación:England
Idioma:eng
Resumen:Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with mixed lineage leukemia (MLL) via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Homeodomain Proteins); 0 (Myeloid Ecotropic Viral Integration Site 1 Protein); 0 (NUP98-HOXA9 fusion protein, human); 0 (Neoplasm Proteins); 0 (Nuclear Pore Complex Proteins); 0 (Oncogene Proteins, Fusion); 149025-06-9 (Myeloid-Lymphoid Leukemia Protein); 157907-48-7 (HoxA protein); EC 2.1.1.43 (Histone-Lysine N-Methyltransferase); EC 2.1.1.43 (Mll protein, mouse)


  2 / 3793 MEDLINE  
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PMID:28174417
Autor:Dang J; Nance S; Ma J; Cheng J; Walsh MP; Vogel P; Easton J; Song G; Rusch M; Gedman AL; Koss C; Downing JR; Gruber TA
Dirección:Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
Título:AMKL chimeric transcription factors are potent inducers of leukemia.
Fuente:Leukemia; 31(10):2228-2234, 2017 Oct.
ISSN:1476-5551
País de publicación:England
Idioma:eng
Resumen:Acute megakaryoblastic leukemia in patients without Down syndrome is a rare malignancy with a poor prognosis. RNA sequencing of fourteen pediatric cases previously identified novel fusion transcripts that are predicted to be pathological including CBFA2T3-GLIS2, GATA2-HOXA9, MN1-FLI and NIPBL-HOXB9. In contrast to CBFA2T3-GLIS2, which is insufficient to induce leukemia, we demonstrate that the introduction of GATA2-HOXA9, MN1-FLI1 or NIPBL-HOXB9 into murine bone marrow induces overt disease in syngeneic transplant models. With the exception of MN1, full penetrance was not achieved through the introduction of fusion partner genes alone, suggesting that the chimeric transcripts possess a unique gain-of-function phenotype. Leukemias were found to exhibit elements of the megakaryocyte erythroid progenitor gene expression program, as well as unique leukemia-specific signatures that contribute to transformation. Comprehensive genomic analyses of resultant murine tumors revealed few cooperating mutations confirming the strength of the fusion genes and their role as pathological drivers. These models are critical for both the understanding of the biology of disease as well as providing a tool for the identification of effective therapeutic agents in preclinical studies.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Oncogene Proteins, Fusion); 0 (RNA, Small Interfering); 0 (Transcription Factors)


  3 / 3793 MEDLINE  
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PMID:28078715
Autor:Sklarz T; Guan P; Gohil M; Cotton RM; Ge MQ; Haczku A; Das R; Jordan MS
Dirección:Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA.
Título:mTORC2 regulates multiple aspects of NKT-cell development and function.
Fuente:Eur J Immunol; 47(3):516-526, 2017 Mar.
ISSN:1521-4141
País de publicación:Germany
Idioma:eng
Resumen:Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictor CD4cre mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-γ production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of developing and mature iNKT-cells. Thus, mTORC2 regulates multiple aspects of iNKT-cell development and function.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Carrier Proteins); 0 (Cytokines); 0 (Multiprotein Complexes); 0 (Proliferating Cell Nuclear Antigen); 0 (Rapamycin-Insensitive Companion of mTOR Protein); 0 (p27 antigen); 0 (rictor protein, mouse); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)


  4 / 3793 MEDLINE  
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PMID:28074064
Autor:Freund P; Kerenyi MA; Hager M; Wagner T; Wingelhofer B; Pham HTT; Elabd M; Han X; Valent P; Gouilleux F; Sexl V; Krämer OH; Groner B; Moriggl R
Dirección:Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Título:O-GlcNAcylation of STAT5 controls tyrosine phosphorylation and oncogenic transcription in STAT5-dependent malignancies.
Fuente:Leukemia; 31(10):2132-2142, 2017 Oct.
ISSN:1476-5551
País de publicación:England
Idioma:eng
Resumen:The signal transducer and activator of transcription 5 (STAT5) regulates differentiation, survival, proliferation and transformation of hematopoietic cells. Upon cytokine stimulation, STAT5 tyrosine phosphorylation (pYSTAT5) is transient, while in diverse neoplastic cells persistent overexpression and enhanced pYSTAT5 are frequently found. Post-translational modifications might contribute to enhanced STAT5 activation in the context of transformation, but the strength and duration of pYSTAT5 are incompletely understood. We found that O-GlcNAcylation and tyrosine phosphorylation act together to trigger pYSTAT5 levels and oncogenic transcription in neoplastic cells. The expression of a mutated hyperactive gain-of-function (GOF) STAT5 without O-GlcNAcylation resulted in decreased tyrosine phosphorylation, oligomerization and transactivation potential and complete loss of oncogenic transformation capacity. The lack of O-GlcNAcylation diminished phospho-ERK and phospho-AKT levels. Our data show that O-GlcNAcylation of STAT5 is an important process that contributes to oncogenic transcription through enhanced STAT5 tyrosine phosphorylation and oligomerization driving myeloid transformation. O-GlcNAcylation of STAT5 could be required for nutrient sensing and metabolism of cancer cells.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Interleukin-3); 0 (Recombinant Fusion Proteins); 0 (STAT5 Transcription Factor); 0 (STAT5A protein, human); 0 (Tumor Suppressor Proteins); 21820-51-9 (Phosphotyrosine); 2ZD004190S (Threonine); V956696549 (Acetylglucosamine)


  5 / 3793 MEDLINE  
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PMID:28057939
Autor:Yao H; Ma Y; Hong Z; Zhao L; Monaghan SA; Hu MC; Huang LJ
Dirección:Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Título:Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm.
Fuente:Leukemia; 31(10):2122-2131, 2017 Oct.
ISSN:1476-5551
País de publicación:England
Idioma:eng
Resumen:Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, yet constitutively active JAK2 mutants are able to drive selective expansion of particular lineage(s) in myeloproliferative neoplasm (MPN). The molecular basis of lineage specificity is unclear. Here, we show that three activating JAK2 mutants with similar kinase activities in vitro elicit distinctive MPN phenotypes in mice by differentially expanding erythroid vs granulocytic precursors. Molecularly, this reflects the differential binding of JAK2 mutants to cytokine receptors EpoR and GCSFR in the erythroid vs granulocytic lineage and the creation of unique receptor/JAK2 complexes that generate qualitatively distinct downstream signals. Our results demonstrate that activating JAK2 mutants can differentially couple to selective cytokine receptors and change the signaling repertoire, revealing the molecular basis for phenotypic differences elicited by JAK2 (V617F) or mutations in exon 12. On the basis of these findings, receptor-JAK2 interactions could represent new targets of lineage-specific therapeutic approaches against MPN, which may be applicable to other cancers with aberrant JAK-STAT signaling.
Tipo de publicación:COMPARATIVE STUDY; JOURNAL ARTICLE
Nombre de substancia:0 (Receptors, Erythropoietin); 0 (Receptors, Granulocyte Colony-Stimulating Factor); 0 (Recombinant Fusion Proteins); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2)


  6 / 3793 MEDLINE  
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PMID:27859216
Autor:Fu JF; Liang ST; Huang YJ; Liang KH; Yen TH; Liang DC; Shih LY
Dirección:Department of Medical Research, Chang Gung Memorial Hospital, and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
Título:Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model.
Fuente:Int J Cancer; 140(5):1159-1172, 2017 Mar 01.
ISSN:1097-0215
País de publicación:United States
Idioma:eng
Resumen:PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11 . To study the impact of PTPN11 cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 , the cells harboring PTPN11 were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11 autonomously differentiated into macrophages (1.8%) in the medium containing IL3. Further studies showed that the cells had an elevated (∼2.9-fold) Csf1 transcription level and secreted more (∼4.5-fold) M-CSF to the medium which can stimulate monocyte/macrophage differentiation of BM cells. Mice transplanted with the cells harboring PTPN11 had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 , the cells harboring PTPN11 had an increased competitive engraftment and clonal expansion in the BM and spleen of recipient mice, although no competitive growth advantage was observed in the in vitro co-culturing assays. The mice transplanted with the MLL/AF10(OM-LZ) cells harboring PTPN11 developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11 -induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11 to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Interleukin-3); 0 (MLL-AF10 fusion protein, human); 0 (Oncogene Proteins, Fusion); 04079A1RDZ (Cytarabine); 149025-06-9 (Myeloid-Lymphoid Leukemia Protein); 81627-83-0 (Macrophage Colony-Stimulating Factor); 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor); EC 3.1.3.48 (PTPN11 protein, human); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11); ZS7284E0ZP (Daunorubicin)


  7 / 3793 MEDLINE  
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PMID:27798146
Autor:Shifrin NT; Kissiov DU; Ardolino M; Joncker NT; Raulet DH
Dirección:Department of Molecular and Cell Biology, Division of Immunology, University of California at Berkeley, Berkeley, CA 94720, USA.
Título:Differential Role of Hematopoietic and Nonhematopoietic Cell Types in the Regulation of NK Cell Tolerance and Responsiveness.
Fuente:J Immunol; 197(10):4127-4136, 2016 Nov 15.
ISSN:1550-6606
País de publicación:United States
Idioma:eng
Resumen:Many NK cells express inhibitory receptors that bind self-MHC class I (MHC I) molecules and prevent killing of self-cells, while enabling killing of MHC I-deficient cells. But tolerance also occurs for NK cells that lack inhibitory receptors for self-MHC I, and for all NK cells in MHC I-deficient animals. In both cases, NK cells are unresponsive to MHC I-deficient cells and hyporesponsive when stimulated through activating receptors, suggesting that hyporesponsiveness is responsible for self-tolerance. We generated irradiation chimeras, or carried out adoptive transfers, with wild-type (WT) and/or MHC I-deficient hematopoietic cells in WT or MHC I-deficient C57BL/6 host mice. Unexpectedly, in WT hosts, donor MHC I-deficient hematopoietic cells failed to induce hyporesponsiveness to activating receptor stimulation, but did induce tolerance to MHC I-deficient grafts. Therefore, these two properties of NK cells are separable. Both tolerance and hyporesponsiveness occurred when the host was MHC I deficient. Interestingly, infections of mice or exposure to inflammatory cytokines reversed the tolerance of NK cells that was induced by MHC I-deficient hematopoietic cells, but not the tolerance induced by MHC I-deficient nonhematopoietic cells. These data have implications for successful bone marrow transplantation, and suggest that tolerance induced by hematopoietic cells versus nonhematopoietic cells may be imposed by distinct mechanisms.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Cytokines); 0 (Histocompatibility Antigens Class I)


  8 / 3793 MEDLINE  
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PMID:27681121
Autor:Parker ZM; Pasieka TJ; Parker GA; Leib DA
Dirección:Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
Título:Immune- and Nonimmune-Compartment-Specific Interferon Responses Are Critical Determinants of Herpes Simplex Virus-Induced Generalized Infections and Acute Liver Failure.
Fuente:J Virol; 90(23):10789-10799, 2016 Dec 01.
ISSN:1098-5514
País de publicación:United States
Idioma:eng
Resumen:The interferon (IFN) response to viral pathogens is critical for host survival. In humans and mouse models, defects in IFN responses can result in lethal herpes simplex virus 1 (HSV-1) infections, usually from encephalitis. Although rare, HSV-1 can also cause fulminant hepatic failure, which is often fatal. Although herpes simplex encephalitis has been extensively studied, HSV-1 generalized infections and subsequent acute liver failure are less well understood. We previously demonstrated that IFN-αßγR mice are exquisitely susceptible to liver infection following corneal infection with HSV-1. In this study, we used bone marrow chimeras of IFN-αßγR (AG129) and wild-type (WT; 129SvEv) mice to probe the underlying IFN-dependent mechanisms that control HSV-1 pathogenesis. After infection, WT mice with either IFN-αßγR or WT marrow exhibited comparable survival, while IFN-αßγR mice with WT marrow had a significant survival advantage over their counterparts with IFN-αßγR marrow. Furthermore, using bioluminescent imaging to maximize data acquisition, we showed that the transfer of IFN-competent hematopoietic cells controlled HSV-1 replication and damage in the livers of IFN-αßγR mice. Consistent with this, the inability of IFN-αßγR immune cells to control liver infection in IFN-αßγR mice manifested as profoundly elevated aspartate transaminase (AST) and alanine transaminase (ALT) levels, indicative of severe liver damage. In contrast, IFN-αßγR mice receiving WT marrow exhibited only modest elevations of AST and ALT levels. These studies indicate that IFN responsiveness of the immune system is a major determinant of viral tropism and damage during visceral HSV infections. IMPORTANCE: Herpes simplex virus 1 (HSV-1) infection is an incurable viral infection with the most significant morbidity and mortality occurring in neonates and patients with compromised immune systems. Severe pathologies from HSV include the blindness-inducing herpetic stromal keratitis, highly debilitating and lethal herpes simplex encephalitis, and generalized infections that can lead to herpes simplex virus-induced acute liver failure. While immune compromise is a known factor, the precise mechanisms that lead to generalized HSV infections are unknown. In this study, we used and developed a mouse model system in combination with real-time bioluminescence imaging to demonstrate the relative importance of the immune and nonimmune compartments for containing viral spread and promoting host survival after corneal infection. Our results shed light on the pathogenesis of HSV infections that lead to generalized infection and acute liver failure.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Receptors, Interferon); 9008-11-1 (Interferons)


  9 / 3793 MEDLINE  
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PMID:27531927
Autor:Melton DW; Roberts AC; Wang H; Sarwar Z; Wetzel MD; Wells JT; Porter L; Berton MT; McManus LM; Shireman PK
Dirección:Department of Surgery, University of Texas Health Science Center, San Antonio, Texas, USA.
Título:Absence of CCR2 results in an inflammaging environment in young mice with age-independent impairments in muscle regeneration.
Fuente:J Leukoc Biol; 100(5):1011-1025, 2016 Nov.
ISSN:1938-3673
País de publicación:United States
Idioma:eng
Resumen:Skeletal muscle regeneration requires coordination between dynamic cellular populations and tissue microenvironments. Macrophages, recruited via CCR2, are essential for regeneration; however, the contribution of macrophages and the role of CCR2 on nonhematopoietic cells has not been defined. In addition, aging and sex interactions in regeneration and sarcopenia are unclear. Muscle regeneration was measured in young (3-6 mo), middle (11-15 mo), old (24-32 mo) male and female CCR2 mice. Whereas age-related muscle atrophy/sarcopenia was present, regenerated myofiber cross-sectional area (CSA) in CCR2 mice was comparably impaired across all ages and sexes, with increased adipocyte area compared with wild-type (WT) mice. CCR2 mice myofibers achieved approximately one third of baseline CSA even 84 d after injury. Regenerated CSA and clearance of necrotic tissue were dependent on bone marrow-derived cellular expression of CCR2. Myogenic progenitor cells isolated from WT and CCR2 mice exhibited comparable proliferation and differentiation capacity. The most striking cellular anomaly in injured muscle of CCR2 mice was markedly decreased macrophages, with a predominance of Ly6C anti-inflammatory monocytes/macrophages. Ablation of proinflammatory TLR signaling did not affect muscle regeneration or resolution of necrosis. Of interest, many proinflammatory, proangiogenic, and chemotactic cytokines were markedly elevated in injured muscle of CCR2 relative to WT mice despite impairments in macrophage recruitment. Collectively, these results suggest that CCR2 on bone marrow-derived cells, likely macrophages, were essential to muscle regeneration independent of TLR signaling, aging, and sex. Decreased proinflammatory monocytes/macrophages actually promoted a proinflammatory microenvironment, which suggests that inflammaging was present in young CCR2 mice.
Tipo de publicación:COMPARATIVE STUDY; JOURNAL ARTICLE
Nombre de substancia:0 (Adaptor Proteins, Vesicular Transport); 0 (Ccr2 protein, mouse); 0 (Cytokines); 0 (Myd88 protein, mouse); 0 (Myeloid Differentiation Factor 88); 0 (Receptors, CCR2); 0 (TICAM-1 protein, mouse)


  10 / 3793 MEDLINE  
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PMID:27455420
Autor:Campisi L; Barbet G; Ding Y; Esplugues E; Flavell RA; Blander JM
Dirección:Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Título:Apoptosis in response to microbial infection induces autoreactive TH17 cells.
Fuente:Nat Immunol; 17(9):1084-92, 2016 Sep.
ISSN:1529-2916
País de publicación:United States
Idioma:eng
Resumen:Microbial infections often precede the onset of autoimmunity. How infections trigger autoimmunity remains poorly understood. We investigated the possibility that infection might create conditions that allow the stimulatory presentation of self peptides themselves and that this might suffice to elicit autoreactive T cell responses that lead to autoimmunity. Self-reactive CD4(+) T cells are major drivers of autoimmune disease, but their activation is normally prevented through regulatory mechanisms that limit the immunostimulatory presentation of self antigens. Here we found that the apoptosis of infected host cells enabled the presentation of self antigens by major histocompatibility complex class II molecules in an inflammatory context. This was sufficient for the generation of an autoreactive TH17 subset of helper T cells, prominently associated with autoimmune disease. Once induced, the self-reactive TH17 cells promoted auto-inflammation and autoantibody generation. Our findings have implications for how infections precipitate autoimmunity.
Tipo de publicación:JOURNAL ARTICLE
Nombre de substancia:0 (Autoantigens); 0 (Histocompatibility Antigens Class II); 130068-27-8 (Interleukin-10)



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