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Total 71 results found since Jan 2013.
Wnt5a Induces ROR1 Dependent Tyrosine Phosphorylation of DOCK2, and Enhanced Activation of ERK to Promote Proliferation of CLL Cells
We examined whether the proline-rich-domain (PRD) of ROR1, and SH3-binding motifs with the PRD that were necessary for these effects. We found that PRD and more specifically proline at 808 position of ROR1 was required to enhance phosphorylation of DOCK2 and activation of ERK1/2 over that seen in MEC1 cells lacking ROR1. We also found that inhibition of Rac using a small molecule inhibitor of Rac1/2 could suppress the capacity of Wnt5a to induce activation of ERK, suggesting that Wnt5a induced activation of Rac was required for activation of ERK. Finally, Wnt5a could not enhance the proliferation of CLL cells when treated ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Kipps, T., Rassenti, L. Z., Widhopf II, G. F., Kipps, T. J. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster III Source Type: research
A Critical Role of Growth Arrest-Specific Gene 6-Mer Axis in the Pathogenesis of Endothelial Damage Contributing to Thrombotic Microangiopathy Associated with Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
Graft-versus-host disease (GVHD) and thrombotic microangiopathy (TMA) are severe complications of allogeneic hematopoietic stem cell transplantation (allo-SCT). Host endothelial cells are targets of alloreactive donor cytotoxic T lymphocytes or various proinflammatory cytokines following allo-SCT, and endothelial damage plays an important role in the pathogenic mechanism(s) of TMA associated with GVHD. However, the detailed mechanism(s) of TMA as well as GVHD have not yet been fully elucidated. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for...
Source: Blood - November 21, 2018 Category: Hematology Authors: Furukawa, M., Xintao, W., Ohkawara, H., Fukatsu, M., Alkebsi, L., Noji, H., Ogawa, K., Ikezoe, T. Tags: 701. Experimental Transplantation: Basic Biology, Pre-Clinical Models: Poster III Source Type: research
Topoisomerase I-DNA Covalent Complexes in Myeloid Malignancies: A Potential Biomarker for Topoisomerase I Inhibitor Sensitivity
Conclusions: Based on recent clinical results, there has been renewed interested in topoisomerase I inhibitors, especially for aggressive and transformed MPNs. Topoisomerase I-DNA complex repair/downregulation has been a hallmark of drug resistance to topoisomerase I inhibitors. Therefore, detecting and quantifying these complexes in treated samples has been hypothesized to provide insight into the drug sensitivity, which is particularly important in camptothecins and platinating agents given their narrow therapeutic windows. Immunodetection techniques using an anti-TopIcc antibody may help predict sensitivity of AML to to...
Source: Blood - November 21, 2018 Category: Hematology Authors: Kohorst, M. A., Flatten, K. S., Peterson, K. L., Schneider, P. A., Correia, C., Pratz, K. W., Smith, B. D., Kaufmann, S. H. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases Source Type: research
Targeting Insulin-like Growth Factor in Multiple Myeloma: Novel Strategies in the Treatment of Proteasome Inhibitor Resistant Cells
Conclusion: The IGF1 signaling pathway is involved in proteasome inhibitor sensitivity and plays a key role in chemokine production of the HUVEC. Our data also suggested that administration of IGF1R inhibitor, linsitinib, might be a powerful strategy against myeloma cells and enhance cytotoxic effects of proteasome inhibitors in those residual MM cells.DisclosuresOhyashiki: MSD,: Honoraria, Research Funding; Bristol Meyer Squibb KK,: Honoraria, Research Funding; Kyowakko Kirin KK,: Research Funding; Celegene KK,: Honoraria, Research Funding; Pfizer KK,: Honoraria, Research Funding; Novartis KK,: Honoraria, Research Funding...
Source: Blood - November 21, 2018 Category: Hematology Authors: Tanaka, Y., Okabe, S., Tauchi, T., Ito, Y., Ohyashiki, K. Tags: 605. Molecular Pharmacology, Drug Resistance-Lymphoid and Other Diseases Source Type: research
Targeting XIAP Via Degradation of MDM-2 By MX69 in Aggressive Lymphomas
Conclusion: Our data suggests that in vitro exposure of a wide variety of B-cell lymphoma cell lines (including BL, DLBCL, MCL or RRCL) to MX69 resulted in anti-tumor activity. Perhaps related to its anti-tumor effects, MX69 inhibited XIAP levels. These findings are similar to prior SiRNA XIAP knockdown experiments. Strong synergistic activity was observed when XIAP was combined with various chemotherapy agents and small molecules inhibitors (such as Venetoclax, ixazomib or ibrutinib). Ex vivo experiments using primary tumor cells isolated from lymphoma patients and lymphoma mouse models are been planned. Targeting Mdm2 an...
Source: Blood - November 21, 2018 Category: Hematology Authors: Khan, S., Runckel, K., Mavis, C., Barth, M. J., Hernandez-Ilizaliturri, F. J. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents Source Type: research
An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe-/- mice and ameliorates anemia and iron overload in murine {beta}-thalassemia intermedia
Key Points
Tmprss6 siRNA induces hepcidin and diminishes iron in hemochromatosis or thalassemia mice, improving the anemia seen in the latter model.
Manipulation of TMPRSS6 with RNAi therapeutics may be an approach to treating iron overload diseases associated with low hepcidin levels.
Source: Blood - February 14, 2013 Category: Hematology Authors: Schmidt, P. J., Toudjarska, I., Sendamarai, A. K., Racie, T., Milstein, S., Bettencourt, B. R., Hettinger, J., Bumcrot, D., Fleming, M. D. Tags: Red Cells, Iron, and Erythropoiesis Source Type: research
EB1, p150Glued, and Clasp1 control endothelial tubulogenesis through microtubule assembly, acetylation, and apical polarization
Vascular tube morphogenesis requires the establishment of endothelial cell (EC) apical–basal polarity in three-dimensional (3D) extracellular matrices. To date, there is little understanding of how EC polarity is controlled during these highly dynamic and rapid morphogenic events. We show that the microtubule tip complex proteins, end binding 1 (EB1), p150Glued, and Clasp1, control human EC tube formation by (1) inducing microtubule assembly and asymmetric cytoskeletal polarization, whereby acetylated and detyrosinated tubulins distribute in a subapical membrane location and filamentous actin distributes basally; (2)...
Source: Blood - April 25, 2013 Category: Hematology Authors: Kim, D. J., Martinez-Lemus, L. A., Davis, G. E. Tags: Vascular Biology Source Type: research
Acute and severe coagulopathy in adult mice following silencing of hepatic antithrombin and protein C production
Mice deficient in the anticoagulants antithrombin (Serpinc1) or protein C (Proc) display premature death due to thrombosis-related coagulopathy, thereby precluding their use in gene function studies and thrombosis models. We used RNA interference to silence Serpinc1 and/or Proc in normal adult mice. The severe coagulopathy that followed combined "knockdown" of these genes is reported. Two days after siRNA injection, thrombi (occlusive) were observed in vessels (large and medium-sized) in multiple tissues, and hemorrhages were prominent in the ocular, mandibular, and maxillary areas. Tissue fibrin deposition and reduction o...
Source: Blood - May 23, 2013 Category: Hematology Authors: Safdar, H., Cheung, K. L., Salvatori, D., Versteeg, H. H., Laghmani, E. H., Wagenaar, G. T. M., Reitsma, P. H., van Vlijmen, B. J. M. Tags: Thrombosis and Hemostasis, Brief Reports Source Type: research
Prolylcarboxypeptidase promotes angiogenesis and vascular repair
Prolylcarboxypeptidase (PRCP) is associated with leanness, hypertension, and thrombosis. PRCP-depleted mice have injured vessels with reduced Kruppel-like factor (KLF)2, KLF4, endothelial nitric oxide synthase (eNOS), and thrombomodulin. Does PRCP influence vessel growth, angiogenesis, and injury repair? PRCP depletion reduced endothelial cell growth, whereas transfection of hPRCP cDNA enhanced cell proliferation. Transfection of hPRCP cDNA, or an active site mutant (hPRCPmut) rescued reduced cell growth after PRCP siRNA knockdown. PRCP-depleted cells migrated less on scratch assay and murine PRCPgt/gt aortic segments had ...
Source: Blood - August 22, 2013 Category: Hematology Authors: Adams, G. N., Stavrou, E. X., Fang, C., Merkulova, A., Alaiti, M. A., Nakajima, K., Morooka, T., Merkulov, S., LaRusch, G. A., Simon, D. I., Jain, M. K., Schmaier, A. H. Tags: Vascular Biology Source Type: research
G protein-dependent basal and evoked endothelial cell vWF secretion
von Willebrand factor (vWF) secretion by endothelial cells (ECs) is essential for hemostasis and thrombosis; however, the molecular mechanisms are poorly understood. Interestingly, we observed increased bleeding in EC-Gα13–/–;Gα12–/– mice that could be normalized by infusion of human vWF. Blood from Gα12–/– mice exhibited significantly reduced vWF levels but normal vWF multimers and impaired laser-induced thrombus formation, indicating that Gα12 plays a prominent role in EC vWF secretion required for hemostasis and thrombosis. In isolated buffer-perfused mouse lun...
Source: Blood - January 16, 2014 Category: Hematology Authors: Rusu, L., Andreeva, A., Visintine, D. J., Kim, K., Vogel, S. M., Stojanovic-Terpo, A., Chernaya, O., Liu, G., Bakhshi, F. R., Haberichter, S. L., Iwanari, H., Kusano-Arai, O., Suzuki, N., Hamakubo, T., Kozasa, T., Cho, J., Du, X., Minshall, R. D. Tags: Thrombosis and Hemostasis, Vascular Biology Source Type: research
Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells
Signals from the tumor microenvironment promote the migration, survival, and proliferation of chronic lymphocytic leukemia (CLL) cells. Rho GTPases control various signaling pathways downstream of microenvironmental cues. Here, we analyze the function of Rac1 in the motility and proliferation of CLL cells. We found decreased transcription of the Rac guanine nucleotide exchange factors Tiam1 and Vav1 in unstimulated peripheral blood CLL cells with almost complete loss of Tiam1 but increased transcription of the potential Rac antagonist RhoH. Consistently, stimulation of CLL cells with the chemokine CXCL12 induced RhoA but n...
Source: Blood - April 3, 2014 Category: Hematology Authors: Hofbauer, S. W., Krenn, P. W., Ganghammer, S., Asslaber, D., Pichler, U., Oberascher, K., Henschler, R., Wallner, M., Kerschbaum, H., Greil, R., Hartmann, T. N. Tags: Lymphoid Neoplasia Source Type: research
DUSP4-mediated accelerated T-cell senescence in idiopathic CD4 lymphopenia
Idiopathic CD4 lymphopenia (ICL) is a rare heterogeneous immunological syndrome of unclear etiology. ICL predisposes patients to severe opportunistic infections and frequently leads to poor vaccination effectiveness. Chronic immune activation, expansion of memory T cells, and impaired T-cell receptor (TCR) signaling have been reported in ICL, but the mechanistic and causative links remain unclear. We show that late-differentiated T cells in 20 patients with ICL displayed defective TCR responses and aging markers similar to those found in T cells from elderly subjects. Intrinsic T-cell defects were caused by increased expre...
Source: Blood - April 16, 2015 Category: Hematology Authors: Bignon, A., Regent, A., Klipfel, L., Desnoyer, A., de la Grange, P., Martinez, V., Lortholary, O., Dalloul, A., Mouthon, L., Balabanian, K. Tags: Immunobiology Source Type: research
Novel Insights Into Systemic Iron Regulation
Iron, an essential element in mammals, is absorbed by duodenal enterocytes, enters the circulation through the iron exporter ferroportin, (FPN), circulates bound to transferrin and is uptaken through Transferrin Receptor 1. If in excess, iron is stored in macrophages and hepatocytes and released when needed. To maintain systemic iron homeostasis and to avoid the formation of "non transferrin bound iron" (NTBI), a highly reactive form which causes organ damage, the liver synthetizes hepcidin that, binding FPN, blocks iron export to the circulation. Hepcidin integrates signals from body iron, erythropoiesis and inflammatory ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Silvestri, L., Pagani, A., Nai, A., Camaschella, C. Tags: Swinging the Iron Pendulum: Loss and Gain Through Blood Donation and Transfusion Source Type: research
Targeting Oncoprotein Translation with Rocaglates in MYC-Driven Lymphoma
Background: c-MYC (MYC) is commonly dysregulated in aggressive B cell lymphomas. MYC associated lymphoma, especially Double Hit lymphoma (DHL) and Double-Expression Lymphoma (DEL) which are characterized by MYC and BCL2 dual overexpression usually present with the inferior outcome as rapid disease progression and poor response to standard chemotherapy regimen. Nevertheless, MYC is considered as an "undruggable" target and targeting strategies such as suppressing MYC transcription by bromodomain (BRD)-4 inhibitors have been widely investigated in both preclinical models and clinical trials. However, increasing evidence has ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, X., Bi, C., Lu, T., Yue, T., Zhang, W., Zhang, X., Cheng, W., Tian, T., Lunning, M. A., Vose, J. M., Pelletier, J., Porco, J. A., Tao, J., Fu, K. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Specific Pathway Inhibitors Source Type: research
hnRNP U and DDX47 Are Novel FANCD2 Interactors That May Help to Resolve R-Loops during Mild Replication Stress
Conclusion: We suggest that FANCD2 protects genome stability by recruiting RNA processing enzymes, including hnRNP U or DDX47, to resolve or prevent accumulation of R-loops induced by transcription-replication collisions during mild replication stress. Thus, our study may provide a novel insight to understand the mechanism of bone marrow failure and leukemogenesis in Fanconi anemia patients.DisclosuresTakaori-Kondo: Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Janssen Pharmaceuticals: Honoraria.
Source: Blood - November 21, 2018 Category: Hematology Authors: Okamoto, Y., Abe, M., Itaya, A., Tomida, J., Takaori-Kondo, A., Taoka, M., Isobe, T., Takata, M. Tags: 508. Bone Marrow Failure: Poster I Source Type: research
