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Total 71 results found since Jan 2013.

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

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

Leukemia cell-targeted STAT3 silencing and TLR9 triggering generate systemic antitumor immunity
Signal transducer and activator of transcription 3 (STAT3) is an oncogene and immune checkpoint commonly activated in cancer cells and in tumor-associated immune cells. We previously developed an immunostimulatory strategy based on targeted Stat3 silencing in Toll-like receptor 9 (TLR9)-positive hematopoietic cells using CpG-small interfering RNA (siRNA) conjugates. Here, we assessed the therapeutic effect of systemic STAT3 blocking/TLR9 triggering in disseminated acute myeloid leukemia (AML). We used mouse Cbfb-MYH11/Mpl-induced leukemia model, which mimics human inv(16) AML. Our results demonstrate that intravenously del...
Source: Blood - January 2, 2014 Category: Hematology Authors: Hossain, D. M. S., Dos Santos, C., Zhang, Q., Kozlowska, A., Liu, H., Gao, C., Moreira, D., Swiderski, P., Jozwiak, A., Kline, J., Forman, S., Bhatia, R., Kuo, Y.-H., Kortylewski, M. Tags: Plenary Papers, Myeloid Neoplasia, Gene Therapy Source Type: research

Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells
Thrombospondin-1 (TSP-1) inhibits growth factor signaling at the receptor level in microvascular endothelial cells (MVEC), and CD36 has been suggested to be involved in this inhibition, but the mechanisms are not known. We hypothesized that CD36-TSP-1 interaction recruits Src homology 2 domain–containing protein tyrosine phosphatase (SHP)-1 to the vascular endothelial growth factor receptor 2 (VEGFR2) signaling complex and attenuates vascular endothelial growth factor (VEGF) signaling. Western blots of anti-CD36 and anti-VEGFR2 immunoprecipitates from VEGF-treated MVEC showed that exposure of the cells to a recombina...
Source: Blood - September 5, 2013 Category: Hematology Authors: Chu, L.-Y., Ramakrishnan, D. P., Silverstein, R. L. Tags: Vascular Biology Source Type: research

DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses
In this study, we find that DEP domain containing mTOR interacting protein (DEPTOR) is expressed in different microvascular ECs in vitro and in vivo, and using a small interfering RNA (siRNA) knockdown approach, we find that it regulates mammalian target of rapamycin complex 1 (mTORC1), extracellular signal-regulated kinase 1/2, and signal transducer and activator of transcription 1 activation in part through independent mechanisms. Moreover, using limited gene arrays, we observed that DEPTOR regulates EC activation including mRNA expression of the T-cell chemoattractant chemokines CXCL9, CXCL10, CXCL11, CX3CL1, CCL5, and ...
Source: Blood - September 5, 2013 Category: Hematology Authors: Bruneau, S., Nakayama, H., Woda, C. B., Flynn, E. A., Briscoe, D. M. Tags: Vascular Biology 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

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

SOX4 is a direct target gene of FRA-2 and induces expression of HDAC8 in adult T-cell leukemia/lymphoma
Previously, we have shown that an AP-1 family member, FRA-2, is constitutively expressed in adult T-cell leukemia/lymphoma (ATL) and, together with JUND, upregulates CCR4 and promotes ATL cell growth. Among the identified potential target genes of FRA-2/JUND was SOX4. Here, we examine the expression and function of SOX4 in ATL. SOX4 was indeed consistently expressed in primary ATL cells. FRA-2/JUND efficiently activated the SOX4 promoter via an AP-1 site. Knockdown of SOX4 expression by small interfering RNA (siRNA) strongly suppressed cell growth of ATL cell lines. Microarray analyses revealed that SOX4 knockdown reduced ...
Source: Blood - May 2, 2013 Category: Hematology Authors: Higuchi, T., Nakayama, T., Arao, T., Nishio, K., Yoshie, O. Tags: Lymphoid Neoplasia 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

TLR9-mediated siRNA delivery for targeting of normal and malignant human hematopoietic cells in vivo
Key Points CpG(A)-siRNA oligonucleotides allow for targeting genes specifically in human TLR9+ immune cells and blood cancer cells. Tumoricidal and immunostimulatory properties of CpG(A)-STAT3 siRNA provide a novel therapeutic opportunity for hematologic malignancies.
Source: Blood - February 21, 2013 Category: Hematology Authors: Zhang, Q., Hossain, D. M. S., Nechaev, S., Kozlowska, A., Zhang, W., Liu, Y., Kowolik, C. M., Swiderski, P., Rossi, J. J., Forman, S., Pal, S., Bhatia, R., Raubitschek, A., Yu, H., Kortylewski, M. Tags: Gene Therapy 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