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Total 71 results found since Jan 2013.

Effective Lipidoid Nanoparticle Delivery In Vivo of siRNA Targeting Kappa Light Chain Production in a Murine Xenograft Model
CONCLUSIONS: We have previously shown that siIGKC, a pool of siRNA directed at consensus sequences in the LC constant region gene, can significantly reduce LC production in clonal plasma cells from patients, in human myeloma cell lines, and in vivo in a flank plasmacytoma xenograft model. In this work, we show that 8B-3 is a promising LPN for delivery of siRNA to human plasma cells and, when loaded with siIGKC, can with relative safety significantly reduce circulating LC in the NSG JJN3 IP model after 3 daily IP injections despite rapid tumor growth. We also show the utility of the NSG JJN3 IP model for the study of LC dir...
Source: Blood - November 21, 2018 Category: Hematology Authors: Ma, X., Zhou, P., Kugelmass, A., Toskic, D., Warner, M., Lee, L. X., Fogaren, T., Wang, M., Li, Y., Yang, L., Xu, Q., Comenzo, R. Tags: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy: Poster II 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

One siRNA pool targeting the {lambda} constant region stops {lambda} light-chain production and causes terminal endoplasmic reticulum stress
In systemic light-chain amyloidosis, light chains produced by clonal plasma cells cause organ damage and early death. In pursuit of novel therapy, we developed 1 pool of short interfering RNA (siRNA) targeting the constant region of light chains that substantially and promptly reduces -light-chain production and secretion by human plasma cells regardless of sequence diversity. In clones producing intact immunoglobulin G (IgG) antibodies (containing paired heavy and light chains), the secretion of intact antibodies is reduced, and all 3 branches of the unfolded protein response are activated by accumulation of unpaired IgG ...
Source: Blood - May 29, 2014 Category: Hematology Authors: Zhou, P., Ma, X., Iyer, L., Chaulagain, C., Comenzo, R. L. Tags: Multiple Myeloma, Lymphoid Neoplasia Source Type: research

Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease
Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80+ macrophages, as well as myofibroblasts expressing HSP47 and retinol-bin...
Source: Blood - March 29, 2018 Category: Hematology Authors: Yamakawa, T., Ohigashi, H., Hashimoto, D., Hayase, E., Takahashi, S., Miyazaki, M., Minomi, K., Onozawa, M., Niitsu, Y., Teshima, T. Tags: Transplantation Source Type: research

SLN124, a Galnac-siRNA Conjugate Targeting TMPRSS6, for the Treatment of Iron Overload and Ineffective Erythropoiesis Such As in Beta-Thalassemia
Accumulation of excess iron in tissues causes organ damage and dysfunction and may lead to serious clinical consequences including liver cirrhosis, diabetes, growth retardation and heart failure. Iron overload is a major health threat in iron loading anemias, like beta-thalassemia, myelodysplastic syndrome and in hereditary hemochromatosis. In patients with beta-thalassemia major, iron overload develops due to frequent blood transfusions to control the severe anemia. In addition, iron overload also occurs in patients with beta thalassemia intermedia (non-transfusion dependent beta-thalassemia). In the later cases, iron ove...
Source: Blood - November 21, 2018 Category: Hematology Authors: Altamura, S., Altamura, S., Muckenthaler, M. U., Dames, S., Frauendorf, C., Schubert, S., Aleku, M., Vadolas, J., Grigoriadis, G., Zugel, U. Tags: 102. Regulation of Iron Metabolism: Poster II Source Type: research

NCOA4 Mediates Mobilization of Hepatic Iron Stores after Blood Loss
The intracellular protein NCOA4 mediates the autophagic degradation of ferritin in vitro (Mancias et al., Nature 2014; Dowdle et al., Nat Cell Biol 2014); mice with global Ncoa4 disruption show hyperferremia, microcytic anemia, and ferritin accumulation in multiple organs, including liver (Bellelli et al., Cell Rep 2016). Here, we dissect the requirement for NCOA4 in hepatic iron mobilization after acute blood loss, using Ncoa4-targeting siRNA that was conjugated to triantennary N-acetylgalactosamine (GalNAc-Ncoa4 siRNA) to promote uptake by hepatocytes. On experimental day 0, 8-week-old female C57BL/6N mice underwent a si...
Source: Blood - November 21, 2018 Category: Hematology Authors: Li, X., Lozovatsky, L., Liu, D., Ayala-Lopez, N., Finberg, K. E. Tags: 102. Regulation of Iron Metabolism: Poster I Source Type: research

Ubiquitin-Activating Enzyme E1 Inhibition Caused Acute Leukemia Cell Apoptosis By Affecting CHOP Pathway
Conclusion: The inhibition of UBE1 activity can induce AML cell apoptosis by endoplasmic reticulum stress CHOP pathway. It will provide new clues for the treatment of acute myeloid leukemia.Disclosures: No relevant conflicts of interest to declare.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Bai, J., He, A., Wang, J., Yang, Y., Shen, Y., Feng, Y., Xu, Y. Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II Source Type: research

HMGB1 Interacts with the MLL-AF4 Fusion Complex to Regulate Pro-Leukemic Gene Transcription in Infant Acute Lymphoblastic Leukemia
In this study, we generated an HMGB1 siRNA knockdown in primary MLL-ALL cells from 3 infants to test our hypothesis that HMGB1-MLL interactions regulate pro-leukemic gene expression and represent a rational therapeutic target.CD19-selected leukemic blasts were isolated from the cryopreserved bone marrow or peripheral blood specimens of 3 infants with cytogenetically confirmed MLL-AF4 rearrangements. HMGB1 knockdown was confirmed by comparing HMGB1 mRNA and protein expression, by qPCR and Western Blot, in cells transfected with HMGB1 vs. control sequence siRNA. First, determined whether HMGB1 knockdown affected expression o...
Source: Blood - November 21, 2018 Category: Hematology Authors: Toia, L. M., Braverman, E. L., Magno, J. A., Shand, J. C. Tags: 602. Disordered Gene Expression in Hematologic Malignancy, including Disordered Epigenetic Regulation: Poster II Source Type: research

The Abnormal Expression and Mutation of Recombination Signal Binding Protein-Jk Gene Mightbe Contribute to the Proliferation of CD59- Clone in Paroxysmal Nocturnal Hemoglobinuria Patients
Conclusion: High expressed RBPJ was associated with hemolysis index in PNH, and inhibiting it can induced the apoptosis of PNH primary cells in vitro, indicating RBPJ may be involved in the proliferation of PNH clones.Figure.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Fu, R., LI, L., Liu, Z., Liu, H., Wang, H., Chen, Y., Shao, Z. Tags: 101. Red Cells and Erythropoiesis, Structure and Function, Metabolism, and Survival, Excluding Iron: Poster III Source Type: research

Endoplasmic Reticulum Stress Signaling Comprises a G9a Inhibitor Tolerance Pathway and PERK Inhibition Increases Anti-Leukemia Activity of G9a Inhibitor in Leukemia Cells and Leukemia Stem-like Cells
Conclusion: These data demonstrated that PERK-eIF2α activation has a pro-survival function to G9a inhibitor in leukemia cells and mediates resistance of AML stem cells to G9a inhibitor treatment. The PERK-eIF2α phosphorylation arm may represent a suitable target for combating resistance to G9a inhibitor in AML. The mechanisms underlying the increased sensitivity of AML cells with PERK inhibition to G9a inhibitor are unclear at present and are needed to define in further studies.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Jang, J., Eom, J.-I., Jeung, H.-k., Seol, S.-Y., Chung, H., Kim, Y. R., Cheong, J.-W., Min, Y. H. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster I Source Type: research

Development of Liver-Specific Thrombopoietin Targeted Sirnas: Impact on Platelet Count, Megakaryocyte Mass, and Hematopoietic Progenitors in Normal and MPN Murine Models
The Thrombopoietin (THPO)/ thrombopoietin receptor (MPL) signaling axis is not only critical for the generation of platelets and megakaryocytes, but also for the maintenance of hematopoietic stem cells (HSC) and the bone marrow niche. MPL is expressed on primitive HSC, HSC progenitors, megakaryocytes, platelets, osteoblasts and osteoclasts, clonal hematopoietic stem cells and many leukemias. THPO production is constitutive but is also increased by inflammatory cytokines. Sustained exposure to high levels of THPO not only enhances platelet production, but also has a profound effect on HSC and the bone marrow microenvironmen...
Source: Blood - November 21, 2018 Category: Hematology Authors: Desai, D., Borodovsky, A., Davis, W. P., Degaonkar, R., Yucius, K., D'Angelo, K., Gedman, P., Williams, D. M., Rogers, O., Zhao, Z. J., Spivak, J. L., Moliterno, A. R. Tags: 635. Myeloproliferative Syndromes: Basic Science: Poster III 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

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice
This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology.
Source: Blood - May 25, 2016 Category: Hematology Authors: Heestermans, M., Salloum-Asfar, S., Salvatori, D., Laghmani, E. H., Luken, B. M., Zeerleder, S. S., Spronk, H. M. H., Korporaal, S. J., Wagenaar, G. T. M., Reitsma, P. H., van Vlijmen, B. J. M. Tags: Phagocytes, Granulocytes, and Myelopoiesis, Platelets and Thrombopoiesis, Thrombosis and Hemostasis Source Type: research

RAB31-Mediated Endosomal Trafficking Is Defective in RUNX1 Haplodeficiency
Conclusions: These studies provide the first evidence that RAB31 is a direct transcriptional target of RUNX1 and a mechanism for RAB31 downregulation in RUNX1 haplodeficient patients. Downregulation of RAB31 or RUNX1 results in impaired endosomal maturation/trafficking, and this may contribute to the defective handling of α-granule proteins recognized in patients with RUNX1 mutations.DisclosuresLambert: Sysmex: Consultancy; Rigel: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; Educational Concepts in Medicine: Consultancy; CSL: Consultancy; Novartis: Membership on an entity's...
Source: Blood - November 21, 2018 Category: Hematology Authors: Jalagadugula, G. S., Mao, G., Goldfinger, L. E., Wurtzel, J., Lambert, M. P., Rao, A. K. Tags: 311. Disorders of Platelet Number or Function: New Insights into the Production and Function of Platelets Source Type: research

Chidamide, a Novel Histone Deacetylase Inhibitor, Inhibits Multiple Myeloma Cells Proliferation through Succinate Dehydrogenase Subunit a
Most patients with multiple myeloma (MM) would finally relapse. Current chemotherapy regimens have limited effect on relapse MM patients. As a new histone deacetylase inhibitor, chidamide has been used in malignancy treatment such as peripheral T-cell lymphoma. However, it is still unknown if chidamide can be used in MM.To determine the target gene of chidamide in MM patients, we performed RNA-Seq analysis using 3 MM patients' bone marrow mononuclear cells. Their BMMCs were cultured with 6μM chidamide or not, and six of the most significantly changed coding genes were selected. Realtime RT-PCR showed that compared with ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Sun, Y., Liu, P., Li, J. Tags: 653. Myeloma: Therapy, excluding Transplantation: Poster I Source Type: research