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- Type:
- Article
- 摘抄:
- Not Available.
- 作者:
- Cancelas, Jose A. and Taniguchi, E.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2012-09-01
- 证书:
- All rights reserved
-
Insertional Mutagenesis Identifies a STAT3/Arid1b/ b-catenin Pathway Driving Neurofibroma Initiation
- Type:
- Article
- 摘抄:
- Wu et al. map an Nf1-Stat3-Arid1b/ b-catenin pathway that initiates Neurofibromatosis type 1 (Nf1) neurofibromas, using unbiased insertional mutagenesis screening. Stat3 transcriptionally represses Gsk3b and Arid1b, thereby activating b-catenin in Schwann cell precursors and resulting in neurofibroma initiation and maintenance. Stat3-mediated modification plays a role in early tumorigenesis.
- 作者:
- Spinner, R. J.; Ratner, N.; Largaespada, D. A.; Keng, V.; Patmore, D. M.; Wu, J., and Cancelas, Jose A.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2016-02
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A ROLE IN TUMOR MAINTENANCE Nancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1, Edwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James R. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose A. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David A. Largaespada2; 1 Cincinnati Children’s, Cincinnati, OH, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3 Mayo Clinic, Rochester, MN, USA; 4 Massachusetts General Hospital, Boston, MA, USA; 5 National Cancer Institute Pediatric Branch, Bethesda, MD, USA; 6 New York University School of Medicine, New York, NY, USA To identify genes and signaling pathways that drive peripheral nerve tumor initiationand growth beyond the Ras-MAPK pathwaywe used unbiased insertional mutagenesis screening. We identified Stat3 as a potential driver of Neurofibromatosis type 1 neurofibroma. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented neurofibroma formation, and self-renewal of tumor initiating cells. Genetic gain- and loss-of-function identified EGFR as the major upstream regulator of P-Stat3 in mouse and human neurofibroma SCP and in neurofibroma initiation; IL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/ Stat3 inhibitor reduced established neurofibroma growth, supporting an additional role for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream of Stat3, we identified b-catenin, and b-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and b-catenin were strongly correlated in NF1 human plexiform neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ b-catenin pathway inhibition in neurofibroma therapeutic trials. Supported by: NIH R01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a DAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.). The American Cancer Society (IRG-67-003-44) supported J.R.F.
- 作者:
- Schwartz, E. B.; Ratner, N.; Largaespada, D. A.; Cancelas, Jose A., and Stemmer-Rachamimov, A. O.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2014-11
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- Overnight, room temperature hold (ONH) of whole blood before component processing offers several benefits. This study evaluated the storage and in vivo recovery characteristics of ONH red blood cells (RBCs) stored in additive solution-7 (AS-7).
- 作者:
- Szczerpiorkowski, Z. M.; Whitley, P.; Maes, L. A.; Dumont, L. J.; Cancelas, Jose A.; Zia, M.; Hess, J. R.; Rugg, N., and Herschel, L.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2014-10
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- Patients in organ failure of vascular origin have increased circulating hematopoietic stem cells and progenitors (HSC/P). Plasma levels of angiotensin II (Ang-II), are commonly increased in vasculopathies. Hyperangiotensinemia results in activation of a very distinct Ang-II receptor set, Rho-family GTPase members, and actin in bone marrow endothelial cells (BMEC) and HSC/P, which results in decreased membrane integrin activation in both BMEC and HSC/P, and in HSC/P de-adhesion and mobilization. The Ang-II effect can be reversed pharmacologically and genetically by inhibiting Ang-II production or signaling through BMEC AT2R, HSCP AT1R/ AT2R or HSC/P RhoA, but not by interfering with other vascular tone mediators. Hyperangiotensinemia and high counts of circulating HSC/P seen in sickle cell disease (SCD) as a result of vascular damage, is significantly decreased by Ang-II inhibitors. Our data define for the first time the role of Ang-II HSC/P traffic regulation and redefine the hematopoietic consequences of anti-angiotensin therapy in SCD.
- 作者:
- Inagami, T.; Hill, S. E.; Wellendorf, A. M.; Perumbeti, A.; Nayak, R. C.; Bezold, K. Y.; Zheng, Y.; Chang, K. H.; Pirman, M.; Loberg, A.; Cancelas, Jose A.; Roy, S.; Malik, P.; Starnes, J., and Zhou, X.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2015-01
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- Chromosome 5q deletions (del[5q]) are common in high-risk (HR) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML); however, the gene regulatory networks that sustain these aggressive diseases are unknown. Reduced miR-146a expression in del(5q) HR MDS/AML and miR-146a/ hematopoietic stem/progenitor cells (HSPCs) results in TRAF6/NF-kB activation. Increased survival and proliferation of HSPCs from miR-146alow HR MDS/AML is sustained by a neighboring haploid gene, SQSTM1 (p62), expressed from the intact 5q allele. Overexpression of p62 from the intact allele occurs through NF-kB-dependent feedforward signaling mediated by miR-146a deficiency. p62 is necessary for TRAF6-mediated NF-kB signaling, as disrupting the p62-TRAF6 signaling complex results in cell-cycle arrest and apoptosis of MDS/AML cells. Thus, del(5q) HR MDS/AML employs an intrachromosomal gene network involving loss of miR-146a and haploid overexpression of p62 via NF-kB to sustain TRAF6/NF-kB signaling for cell survival and proliferation. Interfering with the p62-TRAF6 signaling complex represents a therapeutic option in miR-146a-deficient and aggressive del(5q) MDS/AML.
- 作者:
- Komurov, K.; Maciejewski, J. P.; Bolanos, L.; Grimes, H. L.; Cancelas, Jose A.; Chen, X.; Barker, B.; Weirauch, M. T.; Jerez, A.; Liu, X.; Makishima, H.; Christie, S.; Starczynowski, D. T.; Rao, D. S., and Fang, J.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2014-09
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- Severe congenital neutropenia (SCN) is often associated with inherited heterozygous point mutations in ELANE, which encodes neutrophil elastase (NE). However, a lack of appropriate models to recapitulate SCN has substantially hampered the understanding of the genetic etiology and pathobiology of this disease. To this end, we generated both normal and SCN patient–derived induced pluripotent stem cells (iPSCs), and performed genome editing and differentiation protocols that recapitulate the major features of granulopoiesis. Pathogenesis of ELANE point mutations was the result of promyelocyte death and differentiation arrest, and was associated with NE mislocalization and activation of the unfolded protein response/ER stress (UPR/ER stress). Similarly, high-dose G-CSF (or downstream signaling through AKT/BCL2) rescues the dysgranulopoietic defect in SCN patient–derived iPSCs through C/EBPβ-dependent emergency granulopoiesis. In contrast, sivelestat, an NE-specific small-molecule inhibitor, corrected dysgranulopoiesis by restoring normal intracellular NE localization in primary granules; ameliorating UPR/ER stress; increasing expression of CEBPA, but not CEBPB; and promoting promyelocyte survival and differentiation. Together, these data suggest that SCN disease pathogenesis includes NE mislocalization, which in turn triggers dysfunctional survival signaling and UPR/ER stress. This paradigm has the potential to be clinically exploited to achieve therapeutic responses using lower doses of G-CSF combined with targeting to correct NE mislocalization.
- 作者:
- Lutzko, C.; Mehta, P.; Kalfa, T.; Aronow, B. J.; Myers, K.; Grimes, H. L.; Horwitz, M.; Cancelas, Jose A.; Valencia, C. A.; Trump, L., and Nayak, R. C.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2015-07
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- Not Available
- 作者:
- Moscat, J.; Nayak, R. C.; Aronow, B.; Duran, A., and Cancelas, Jose A.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2014-12
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- Not Available
- 作者:
- Maes, L. A.; Rugg. N; Dumont, L. J.; Cancelas, Jose A.; Zia, M.; Hess, J. R.; Whitley, P. H.; Siegel, A. H.; Szczepiokowski, Z. M., and Herschel, L.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2014-10
- 证书:
- All rights reserved
-
- Type:
- Article
- 摘抄:
- Not Available
- 作者:
- Rugg, N. and Cancelas, Jose A.
- 提交者:
- Jose Cancelas
- 上传日期:
- 02/08/2017
- 更改日期:
- 04/10/2017
- 创建:
- 2016-10-04
- 证书:
- All rights reserved