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Total 71 results found since Jan 2013.
CSF1R inhibitors exhibit antitumor activity in acute myeloid leukemia by blocking paracrine signals from support cells
This study identifies CSF1R as a novel therapeutic target of AML and provides a mechanism of paracrine cytokine/growth factor signaling in this disease.
Source: Blood - February 7, 2019 Category: Hematology Authors: Edwards, D. K., Watanabe-Smith, K., Rofelty, A., Damnernsawad, A., Laderas, T., Lamble, A., Lind, E. F., Kaempf, A., Mori, M., Rosenberg, M., dAlmeida, A., Long, N., Agarwal, A., Sweeney, D. T., Loriaux, M., McWeeney, S. K., Tyner, J. W. Tags: Myeloid Neoplasia Source Type: research
CD55 and CD59 Can Limit the Anti-Tumor Efficacy of Daratumumab in Natural Killer/T-Cell Lymphoma
In this report we show that subsequent testing in an NKTL mouse xenograft model confirms the potency of Daratumumab in vivo as evidenced by the inhibition in tumour progression and prolongation of mouse survival. When treatment was continued over a month, some tumors began to rapidly enlarge ('Resistant') while the rest remained similar or smaller ('Sensitive') than the tumour volume at the initiation of Daratumumab treatment. An mRNA analysis comparing 'Resistant' and 'Sensitive' tumors showed that while both tumours bore similar levels of CD38 expression, resistant tumours displayed an upregulation of complement inhibito...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mustafa, N., Nee, A. H. F., Chooi, J. Y., Toh, S. H. M., Hee, Y. T., Selvarajan, V., Zhou, L., Yang, J., Chng, W. J. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Poster I Source Type: research
PKM2 Mediates Chronic Myeloid Leukemia Imatinib Resistance By Regulating Glycolysis Energy Metabolism
Conclusion: Pyruvate kinase M2 (PKM2) acts as an important rate-limiting enzyme in the aerobic glycolytic pathway, and mediates abnormal metabolic pathways which promote tumor cell proliferation, invasion and drug resistance. Compared to the TKI-sensitive primary cell and cell line, PKM2 was increased in the TKI-resistant primary cell and cell line and related to glycolytic level. PKM2 inhibitor can inhibit CML cells growth, induce cell apoptosis, and combined with IM at a low dose can exhibited a synergistic anti-leukemia effect on TKI-resistant cells. Low dose PKM2 inhibitor combined with IM can enhance targeted killing ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Tong, L., Xu, N., Zhou, X., Huang, J., wan-Er, W., Chen, C., Liang, L., Liu, Q., Xiaoli, L. Tags: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research
Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Induces Genetic Instability and Can be Therapeutically Targeted
In conclusion, phosphorylation by Aurora Kinase A and ubiquitination by MDM2 contribute to SETD2 non-genomic loss of function in advanced-phase CML. Loss of SETD2/H3K36me3 is associated with increased DNA damage and impaired HR repair. Restoring physiological H3K36me3 levels may help improve the outcome of this critical subset of pts.Acknowledgments: study supported by AIRC (project code 16996) and AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma).Figure 1.DisclosuresCastagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consulta...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mancini, M., De Santis, S., Monaldi, C., Bavaro, L., Martelli, M., Castagnetti, F., Gugliotta, G., Rosti, G., Fontana, M. C., Dan, E., Sinigaglia, B., Iurlo, A., Orofino, N., Abruzzese, E., Salvucci, M., Pregno, P., Gozzini, A., Crugnola, M., Albano, F., Tags: 631. Chronic Myeloid Leukemia: Biology and Pathophysiology, excluding Therapy: Poster I 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
Role of Arsenic Trioxide in EVI-1 Apoptosis in Patients with Acute Myeloid Leukaemia
Conclusion:Our study demonstrated that the apoptotic pathway in THP-1 cells induced by ATO is closely associated with the oncogene EVI-1, the pro-apoptotic protein JNK, p-JNK, p-P53, PUMA, Bax, caspase-9 and caspase-3 (including cleaved caspase-9 and cleaved caspase-3), and the anti-apoptotic proteins Bcl-2 and Bcl-xL. ATO can downregulate EVI-1 mRNA and oncoprotein and block the repression of EVI-1 in the JNK pathway. Furthermore, the activated JNK signalling pathway regulated the expression level of apoptosis-associated proteins, including p-P53, PUMA, Bax, Bcl-xL, Bcl-2, Bax, caspase-9 and caspase-3(Fig 6). These findin...
Source: Blood - November 21, 2018 Category: Hematology Authors: Lang, W., Chen, F., Zhou, L. Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster I Source Type: research
MDM2 and Aurora Kinase a Contribute to SETD2 Loss of Function in Advanced Systemic Mastocytosis: Implications for Pathogenesis and Treatment
The SETD2 gene encodes the only methyltransferase responsible for histone H3 lysine 36 trimethylation (H3K36Me3) in humans. H3K36me3 play a key role in preserving the fidelity of transcription elongation and splicing. In addition, SETD2/H3K36me3 have more recently been implicated in the maintenance of genomic integrity by regulating homologous recombination (HR) repair, Mismatch Repair (MMR) mitotic spindle assembly and chromosome segregation. SETD2 deletions and/or inactivating mutations occur in many solid tumors and have recently been found also in acute leukemias. We have reported that the HMC-1.1 and -1.2 mast cell le...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mancini, M., Monaldi, C., De Santis, S., Papayannidis, C., Rondoni, M., Bavaro, L., Martelli, M., Maria Chiara, A., Curti, A., Ficarra, E., Paciello, G., Fontana, M. C., Zanotti, R., Bonifacio, M., Scaffidi, L., Pagano, L., Criscuolo, M., Albano, F., Cice Tags: 635. Myeloproliferative Syndromes: Basic Science: Poster I 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
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
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
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
Musashi 2 Is Overexpressed in Poor Outcome CLL Patients and Their Proliferative Fraction and Silencing This Gene Induces Apoptosis and Increases Cell Adhesion and Movement
The growth of CLL cells stems from a small fraction of dividing CD5+B cells. The size and rate of growth of this proliferative fraction (PF) correlates directly with poor outcome prognostic markers and inversely with time-to-first-treatment. Furthermore, since dividing cells upregulate DNA mutators (AID and APOBEC), the PF can acquire new DNA abnormalities that can lead to more lethal disease. Hence, cells of the PF are important targets for therapy.By gene expression profile analysis, we found that Musashi 2 (MSI2) is highly expressed in the PF (CXCR4DimCD5Bright) compared with the resting fraction (RF) that expresses the...
Source: Blood - November 21, 2018 Category: Hematology Authors: Palacios, F., Yan, X.-J., Ferrer, G., Barrientos, J. C., Kolitz, J. E., Allen, S. L., Kanti R., R., Chiorazzi, N. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I Source Type: research
SF3B1 Mutations Associate with Low CD20 Expression in CLL: Another NOTCH1-Dependent Mechanism?
ConclusionsIn addition to NOTCH1-mut cases, also CLL cases bearing SF3B1 mutations are characterized by a lower CD20 expression, allegedly through a more active NOTCH1 pathway, potentially resulting in clinical resistance to anti-CD20 monoclonal antibodies.DisclosuresZaja: Amgen: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Sandoz: Honoraria; Abbvie: Honoraria.
Source: Blood - November 21, 2018 Category: Hematology Authors: Pozzo, F., Bittolo, T., Tissino, E., Vit, F., Vendramini, E., Bomben, R., Zucchetto, A., Dal Bo, M., Laurenti, L., D'Arena, G. F., Di Raimondo, F., Chiarenza, A., Pozzato, G., Zaja, F., Del Poeta, G., Gattei, V. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I 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
Inhibition of B-Cell Receptor Signaling Disrupts Cell Adhesion in Mantle Cell Lymphoma Via RAC2
Conclusions: Our findings uncover a novel cross-talk between BCR signaling and cell adhesion. Ibrutinib inhibits cell adhesion via down-regulation of RAC2. Our study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and new drug development.DisclosuresWang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; AstraZeneca: Consultancy, Research Funding; MoreHealth: Consultancy; Pharmacyclics: Honoraria, Research Funding; Novartis: Research Funding; Dava Oncology: Honoraria; Celgene: Honoraria, Membership on an en...
Source: Blood - November 21, 2018 Category: Hematology Authors: Wang, W., Carrie, F., Guo, H., Lee, J., Li, Y., Sukhanova, M., Sheng, D., Venkataraman, G., Mei, M., Lu, P., Gao, A., Xia, C., Jia, L., Zhang, L., Wang, M., Andrade, J., Xiaoyan, Z., Wang, Y. L. L. Tags: 605. Molecular Pharmacology, Drug Resistance-Lymphoid and Other Diseases: Poster I Source Type: research
