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Experimental Hematology

Bilal N Sheikh, Donald Metcalf, Anne K Voss, Tim Thomas
Chromatin plays a central role in maintaining hematopoietic stem cells and during their stepwise differentiation. While a large number of histone modifications and chromatin modifying enzymes have been identified, how these act in concert to produce specific phenotypic outcomes remains to be established. MOZ (KAT6A) is a lysine acetyltransferase and enhances transcription at target gene loci. In contrast, the polycomb group protein BMI1 (PCGF4) is part of the transcriptionally repressive PRC1 complex. Despite their opposing effects on transcription, MOZ and BMI1 regulate biological systems in a similar manner...
October 20, 2016: Experimental Hematology
Marco Tucci, Stefania Stucci, Anna Passarelli, Stella D'Oronzo, Franco Silvestris
Interleukin-17A (IL-17A) promotes the osteoclast (OC)-like differentiation of dendritic cells (DCs) in multiple myeloma (MM), and contributes to the pathogenesis of myeloma bone disease (MBD). In our study, EVR significantly abrogated the in vitro OC-like activity of DCs from 12 MM patients. Exploring the EVR effects, we found that the inhibition of the osteo-erosive activity of OC-DCs was mostly due to the blockade of signals driven by the IL-17A receptor toward CEBPbeta/MAFB axis Therefore, MM patients with MBD would probably benefit from mTOR inhibition...
October 17, 2016: Experimental Hematology
Janet Ayello, Jessica Hochberg, Allyson Flower, Yaya Chu, Laxmi V Baxi, William Quish, Carmella van de Ven, Mitchell S Cairo
NK cells play a significant role in reducing relapse in patients with hematological malignancies following allogeneic stem cell transplantation but NK cell number and naturally occurring inhibitory signals limit their capability. IL-15 and 4-1BBL are important modulators of NK expansion and functional activation. With an aim to overcome these limitations, cord blood (CB) mononuclear cells (MNC) were ex-vivo expanded (EvE) for 7 days with genetically modified K562-mbIL15-41BBL (MODK562) or wildtype K562 (WTK562)...
October 17, 2016: Experimental Hematology
Janice H C Plani-Lam, Neli S Slavova-Azmanova, Nicole Kucera, Alison Louw, Jiulia Satiaputra, Peter Singer, Kong-Peng Lam, Margaret L Hibbs, Evan Ingley
No abstract text is available yet for this article.
October 14, 2016: Experimental Hematology
Sung-Eun Lim, Virginie Esain, Wanda Kwan, Lindsay N Theodore, Mauricio Cortes, Isaura M Frost, Sarah Y Liu, Trista E North
Hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate into all the mature blood cell lineages and thereby reconstitute the entire blood system. As such, HSCs are therapeutically valuable for treatment of hematological malignances and bone marrow failure. We recently showed that transient glucose elevation elicited dose-dependent effects on HSCs through elevated metabolic activity and subsequent ROS-mediated induction of Hypoxia Inducible Factor 1α (Hif1α). Platelet Derived Growth Factor B (pdgfb), a Hif1α-target, and its receptor, pdgfrb, were significantly upregulated in response to metabolic stimulation...
October 14, 2016: Experimental Hematology
Lei Zhou, Qian Wang, Xiaosu Chen, Lin Fu, Xiaodong Zhang, Lijun Wang, Ailing Deng, Dandan Li, Jing Liu, Na Lv, Lili Wang, Yonghui Li, Daihong Liu, Li Yu, Liping Dou
SIRT1 has been recently found to play an important role in a variety of solid and hematologic malignancies. The expression and function of SIRT1 may be completely different depending on cell type and gene subtype and it can act as a tumor suppressor or oncogene. In this study, we show that SIRT1 mRNA and protein levels are overexpressed in t(8;21) AML cells. AML1-ETO triggers the activation of SIRT1 by binding at AML1-binding sites on SIRT1 promoter. Pharmacologic targeting or RNAi-mediated inhibition of SIRT1 induce G1 arrest, apoptosis, and proliferation inhibition that is more sensitive in AML1-ETO positive cell lines than the negative...
October 7, 2016: Experimental Hematology
Adam P Deveau, Victoria L Bentley, Jason N Berman
Current treatment strategies for acute leukemias largely rely on nonspecific cytotoxic drugs that result in high therapy-related morbidity and mortality. Cost effective, pertinent animal models are needed to link in vitro studies with the development of new therapeutic agents in clinical trials on a high-throughput scale. However, targeted therapies have had limited success moving from bench-to-clinic, often due to unexpected off-target effects. The zebrafish has emerged as a reliable in vivo tool for modeling human leukemia...
October 6, 2016: Experimental Hematology
Ewa Jablonska, Patryk Gorniak, Maciej Szydlowski, Tomasz Sewastianik, Emilia Bialopiotrowicz, Anna Polak, Krzysztof Warzocha, Przemyslaw Juszczynski
B-cell receptor (BCR) signaling plays pivotal role in the pathogenesis of diffuse large B-cell lymphomas (DLBCL), and targeting the BCR pathway is a highly promising therapeutic strategy in this malignancy. Oncogenic microRNA miR-17-92 modulates multiple cellular processes such as survival, proliferation, apoptosis, angiogenesis and BCR signaling. In the present study, we identified new targets of miR-17-92, PTPROt and PP2A phosphatases, which regulate SYK and AKT activity- critical components of BCR signal transduction in DLBCL cells...
October 6, 2016: Experimental Hematology
Keisuke Kataoka, Seishi Ogawa
RHOA is one of the most extensively investigated members of the Rho GTPase family of proteins and has long been implicated in malignant transformation as well as tumor invasion and metastasis. Recently, revolutionized sequencing platforms have revealed frequent RHOA mutations in a wide variety of human cancers, including angioimmunoblastic T-cell lymphoma, adult T-cell leukemia/lymphoma, germinal center B-cell lymphoma, diffuse-type gastric cancer, and other solid tumors. With their discrete positional distributions and types of amino acid substitution depending on cancer type, different RHOA mutations seem to have unique functional and biological properties...
September 29, 2016: Experimental Hematology
Breann Yanagisawa, Gabriel Ghiaur, B Douglas Smith, Richard J Jones
Considerable evidence suggests that rare leukemia cells with stem cell features, including self-renewal capacity and drug resistance, are primarily responsible for both disease maintenance and relapses. Traditionally, these so-called leukemia stem cells (LSCs) have been identified in the laboratory by their ability to engraft acute myeloid leukemia (AML) into immunocompromised mice. For many years, only those rare AML cells characterized by a hematopoietic stem cell (HSC) CD34(+)CD38(-) phenotype were believed capable of generating leukemia in immunocompromised mice...
September 28, 2016: Experimental Hematology
Sarvari Velaga, Christina Alter, Ulrike Dringenberg, Christina T Thiesler, Sandra Kuhs, Sven Olek, Sya N Ukena, Anke Franzke
OBJECTIVE: Recent clinical trials have shown the high potential of regulatory T cells (Tregs) in prevention of acute and chronic graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation but immune interventions require high Treg cell numbers. With respect to limited natural occurrence, development and optimization of large-scale expansion protocols of clinical-grade Tregs are essential if considered for therapeutic use. METHODS: We compared different clinical grade large-scale expansion protocols for repetitive transfer of high Treg cell numbers in clinical trials for the prevention of acute and/or chronic GvHD...
September 27, 2016: Experimental Hematology
Meerim Park, Chan-Jeoung Park, Young Wook Cho, Seongsoo Jang, Jung-Hee Lee, Je-Hwan Lee, Kyoo-Hyung Lee, Young Ho Lee
Hematopoiesis involves complex interactions between hematopoietic cells and the bone marrow (BM) microenvironment; the specific causes and mechanisms underlying dysregulated hematopoiesis are unknown. Here, BM biopsy specimens from patients with aplastic anemia (AA), chronic myeloid leukemia (CML), and normal marrow were analyzed by semiquantitative immunohistochemistry to determine changes in the hematopoietic stem cell (HSC) compartment and BM microenvironment. HSC levels were lowest in AA and highest in CML...
September 27, 2016: Experimental Hematology
Rachael J M Bashford-Rogers, Anne L Palser, Clare Hodkinson, Joanna Baxter, George A Follows, George S Vassiliou, Paul Kellam
Chronic lymphocytic leukaemia (CLL) is characterised by the accumulation of clonally-derived mature CD5(high) B-cells, however the cellular origin of CLL is still unknown. Patients with CLL also harbour variable numbers of CD5(low) B-cells, but the clonal relationship of these cells to the bulk disease is unknown and can have important implications for monitoring, treating and understanding the biology of CLL. Here we use B-cell receptors (BCRs) as molecular barcodes to first show that the great majority of CD5(low) B-cells in the blood of CLL patients are clonally related to CD5(high) CLL B-cells by single-cell BCR sequencing...
September 27, 2016: Experimental Hematology
Alessandra Giorgetti, Julio Castaño, Clara Bueno, Rafael Diaz de la Guardia, Mario Delgado, Anna Bigas, Lluis Espinosa, Pablo Menendez
Recent studies in zebrafish and mice demonstrated that proinflammatory signaling is a positive regulator of definitive hematopoietic development. Whether proinflammatory signaling regulates also human hematopoietic specification remains unknown. Here, we explored the impact of the proinflammatory cytokines tumor necrosis factor-α (TNFα), interferon-γ (IFNγ) and interleukin-1β (IL1β) on in vitro hematopoietic differentiation using human pluripotent stem cells (hPSCs). Gene expression analysis and ELISA revealed the absence of a proinflammatory signature during hematopoietic development of hPSCs...
September 27, 2016: Experimental Hematology
Xiaoyu An, Jinping Liu, Na Wang, Di Wang, Liang Huang, Likun Zhang, Jie Cai, Jean-Pierre Wery, Demin Zhou, Jianfeng Zhou, Qi-Xiang Li
Engrafting a M5-AML patient bone marrow (BM) cells into immunocompromised mice (AM7577) achieved serially transferrable stable AML and eventual mortality. The disease starts at BM followed by expansion to peripherals, typical of M5 leukemogenesis, where high leukemic burden in blood is coincident with symptoms/mortality. The leukemic cells in mice have similar myeloid morphology, phenotypes and genotypes (including FLT3-ITD) as the original patient. Autocrine mechanisms of human GM-CSF/IL-3 likely support AM7577 growth in mice...
September 23, 2016: Experimental Hematology
Ashok Kumar Jayavelu, Jennifer N Moloney, Frank-D Böhmer, Thomas G Cotter
In different types of myeloid leukemia, increased formation of reactive oxygen species (ROS) has been noted and associated with aspects of cell transformation, including the promotion of leukemic cell proliferation and migration, as well as DNA damage and accumulation of mutations. Work reviewed in this article has revealed the involvement of NADPH oxidase (NOX)-derived ROS downstream of oncogenic protein-tyrosine kinases in both processes, and the related pathways have been partially identified. FMS-like tyrosine kinase 3 with internal tandem duplications (FLT3-ITD), an important oncoprotein in a subset of acute myeloid leukemias, causes activation of AKT and, subsequently, stabilization of p22(phox), a regulatory subunit for NOX1-4...
September 22, 2016: Experimental Hematology
Emma L Cambridge, Zoe McIntyre, Simon Clare, Mark J Arends, David Goulding, Christopher Isherwood, Susana S Caetano, Carmen Ballesteros Reviriego, Agnieszka Swiatkowska, Leanne Kane, Katherine Harcourt, David J Adams, Jacqueline K White, Anneliese O Speak
No abstract text is available yet for this article.
September 22, 2016: Experimental Hematology
Robin R Weidemann, Rayk Behrendt, Kristina B Schoedel, Werner Müller, Axel Roers, Alexander Gerbaulet
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and, in most cases, is of pro- or pre-B cell origin (B-ALL). The receptor tyrosine kinase KIT is expressed by hematopoietic stem and precursor cells. Gain-of-function mutations of KIT cause systemic mastocytosis, which is characterized by abnormal accumulations of mast cells. We previously reported a mouse model of mastocytosis based on conditional expression of a constitutively active Kit protein. Half of these animals developed leukemic disease of B-lineage origin...
September 21, 2016: Experimental Hematology
Sisi Chen, Rui Gao, Michihiro Kobayashi, Hao Yu, Chonghua Yao, Reuben Kapur, Mervin C Yoder, Yan Liu
Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplantation remains limited by the inability to expand functional HSCs ex vivo. To determine the role of phosphoinositide 3-kinase (PI3K)/AKT signaling in human hematopoietic stem and progenitor cell (HSPC) maintenance, we examined the effect of genetic and pharmacological inhibition of AKT on human umbilical cord blood (UCB) CD34(+) cells. We found that knock-down of AKT1 in human UCB CD34(+) cells using short interfering RNAs targeting AKT1 enhances their quiescence and colony formation potential in vitro...
September 17, 2016: Experimental Hematology
Edith Schneider, Anna Staffas, Linda Röhner, Kathrin Krowiorz, Michael Heuser, Konstanze Döhner, Lars Bullinger, Hartmut Döhner, Linda Fogelstrand, Arefeh Rouhi, Florian Kuchenbauer, Lars Palmqvist
MicroRNA-155 (miR-155) is an oncogenic miRNA upregulated in various tumor types and leukemias and has been suggested as a potential drug target. Based on our previous work detecting high miR-155 levels in response to Meis1 overexpression in a murine Hox leukemia model, we show here the relationship among HOXA9, MEIS1, and miR-155 levels in MLL-translocated acute myeloid leukemia (AML) patients. Using mouse bone marrow cells transformed by MLL-fusion genes expressing graduated levels of Meis1, we show a positive correlation between miR-155 and Meis1...
September 13, 2016: Experimental Hematology
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