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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

Loss of KDM6A Confers Drug Resistance in Acute Myeloid Leukemia
In conclusion, our results show that mutations in KDM6A are associated with the outgrowth of drug-resistant clones and highlight KDM6A as a novel biomarker of drug resistance in AML.DisclosuresHiddemann: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Metzeler: Novart...
Source: Blood - November 21, 2018 Category: Hematology Authors: Stief, S. M., Hanneforth, A.-L., Mattes, R., Weser, S., Vick, B., Bartoschek, M. D., Dominguez Moreno, H., Liu, W.-H., Ksienzyk, B., Rothenberg-Thurley, M., Quentmeier, H., Hiddemann, W., Metzeler, K. H., Schotta, G., Bultmann, S., Jeremias, I., Leonhardt Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster III Source Type: research

Targeted Delivery of CpG-Mir-146a Mimic Oligonucleotides As a Therapeutic Strategy to Reduce NF-Kb-Mediated Pathogenic Inflammation and Myeloid Leukemia Progression
NF-kB signaling plays central role in the regulation of immune cell activity. The microRNA-146a-5p (miR-146a) provides negative feedback inhibition of the NF-kB pathway to prevent either excessive immunity, such as cytokine release syndrome. Low expression of miR-146a is also implicated in certain types of leukemia, especially in del(5q)-syndrome myelodysplastic and acute myeloid leukemia (MDS/AML). While miR-146a is a potential therapeutic target, the lack of efficient miRNA delivery methods limits clinical translation. We previously developed a strategy for targeted delivery of oligonucleotide therapeutics, such as siRNA...
Source: Blood - November 21, 2018 Category: Hematology Authors: SU, Y.-L., Zhang, Z., Mann, M., Wang, X., Nguyen, L. X. T., Zhang, B., Li, L., Swiderski, P., Boldin, M., Forman, S. J., Marcucci, G., Kortylewski, M. Tags: 802. Chemical Biology and Experimental Therapeutics: Poster II 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

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

Functional Analysis of CD99 Upregulation in Acute Myeloid Leukemia
Conclusion: In summary, our results suggests that even though CD99 enhances AML cell proliferation, it also enhances homotypic cell interaction and cell aggregation, which results in increased cell apoptosis as well as a decrease in cell migration and possibly responsible for the decrease leukemia engraftment. Further investigations are ongoing to determine the effect of homotypic interaction of CD99 in AML.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Vaikari, V. P., Yang, J., Akhtari, M., Alachkar, H. Tags: 603. Oncogenes and Tumor Suppressors 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

The Novel Tumor Suppressor SAMHD1 Is Differentially Expressed and Partly Regulated By MYC in Peripheral T-Cell Lymphomas (PTCL)
Conclusions: SAMHD1 is shown for the first time to be differentially expressed among PTCL types and its regulation may involve MYC. Preliminary survival analysis shows no significant associations of SAMHD1 expression with EFS and OS in this cohort of PTCL, however, analysis of a larger PTCL study group is underway to draw definite conclusions.DisclosuresÖsterborg: Gilead: Consultancy, Research Funding; Beigene: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Abbvie: Research Funding.
Source: Blood - November 21, 2018 Category: Hematology Authors: Farrajota Neves Da Silva, P., Tsesmetzis, N., Xagoraris, I., Wasik, A. M., Kokaraki, G., Tzoras, E., Osterborg, A., Sander, B., Herold, N., Rassidakis, G. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster III Source Type: research

SAMHD1 Is Variably Expressed in Mantle Cell Lymphoma and Correlated to SOX11 but Not to Survival
ConclusionsIn MCL the expression of SAMHD1 varies over a broad range and correlates to expression of SOX11. However, no significant difference in PFS or OS among patients receiving Ara-C containing induction chemotherapy is found in this study.DisclosuresNo relevant conflicts of interest to declare.
Source: Blood - November 21, 2018 Category: Hematology Authors: Wasik, A. M., Marin, E., Merrien, M., de Matos Rodrigues, J., Lord, M., Xagoraris, I., Christensson, B., Rassidakis, G., Jerkeman, M., Ek, S., Sander, B. Tags: 622. Lymphoma Biology-Non-Genetic Studies: Poster III Source Type: research

Concomitant Targeting of FLT3 and BTK with CG'806 Overcomes FLT3-Inhibitor Resistance through Inhibition of Autophagy
Fms-like tyrosine kinase 3 (FLT3)-targeted therapy represents an important paradigm in the management of patients with highly aggressive FLT3 mutated acute myeloid leukemia (AML). However, clinical efficacy is usually transient and followed by emergence of resistance to FLT3-inhibitors (Borthakur et al., 2011; Cortes et al., 2013; Zhang et al., 2008). Such resistance often results from acquired mutations of TKD, which are frequently identified in D835, Y842 and F691 residues (Smith et al., 2015; Smith et al., 2012; Zhang et al., 2014). It was reported that the FLT3-ITD-targeting drug sorafenib can induce autophagy in human...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, W., Yu, G., Zhang, H., Ly, C., Yuan, B., Ruvolo, V., Piya, S., Bhattacharya, S., Zhang, Q., Borthakur, G., Battula, V. L., Konopleva, M. Y., Rice, W. G., Andreeff, M. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Poster II 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

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