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Experimental Hematology

Stephen Capone, Kwasi M Connor, Anthony Colombo, Xin Li, Tim J Triche, Giridharan Ramsingh
Genomic transposable elements (TEs) constitute majority of the genome. Expression of TEs is known to activate the double-stranded RNA recognition pathway ("viral mimicry") leading to the activation of interferon-stimulated genes, inflammation and immune mediated cell death. We recently showed that the expression of TEs is suppressed along with immune pathways in leukemic stem cells (LSC) in acute myeloid leukemia, suggesting a potential mechanism for immune escape of LSC. This indicated that during oncogenesis, where there is escape from senescence, expression of TEs is suppressed...
March 13, 2018: Experimental Hematology
Guillermo Ortí, Jaime Sanz, Irene García-Cadenas, Isabel Sánchez-Ortega, Laura Alonso, Maria José Jiménez, Luisa Sisinni, Carmen Azqueta, Olga Salamero, Isabel Badell, Christelle Ferra, Cristina Diaz de Heredia, Rocio Parody, Miguel Angel Sanz, Jorge Sierra, Jose Luis Piñana, Sergi Querol, David Valcárcel
Relapse of acute leukemia (AL) after allogeneic hematopoietic cell transplantation (Allo-HCT) entails a dismal prognosis. In this scenario, donor lymphocyte infusions (DLI) and second Allo-HCT are two major approaches. We compared outcomes of AL patients treated for relapse with DLI or second Allo-HCT, after receiving debulking therapy. In total, forty-six patients were included in the study, thirty (65%) had AML and sixteen (35%) had ALL. The median age was 38 years (range 4-66). Twenty-seven patients received a second Allo-HCT and 19 patients received DLI...
March 8, 2018: Experimental Hematology
Maile K Hollinger, Valentina Giudice, Nicole A Cummings, Guillermo Rivell, Hansheng Zhang, Sachiko Kajigaya, Keyvan Keyvanfar, Jichun Chen, Xingmin Feng, Neal S Young
While PD-1 blockade has revolutionized cancer immunotherapy, immune-related adverse events (irAEs) present life-threatening complications. Recent reports of aplastic anemia (AA) as irAEs implicate PD-1/PD-L1 as important in preventing immune-mediated destruction of the hematopoietic niche. Infusion of PD-1-deficient (PD-1 KO) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe BM hypoplasia, anemia, and BM microarchitecture disruption in PD-1 KO LN-infused mice relative to mice that received B6 LN cell infusion...
March 7, 2018: Experimental Hematology
Naoya Uchida, Juan J Haro-Mora, Selami Demirci, Atsushi Fujita, Lydia Raines, Matthew M Hsieh, John F Tisdale
A reliable cell line capable of robust in vitro erythroid differentiation would be useful to investigate red blood cell (RBC) biology and genetic strategies for RBC diseases. K562 cells are widely utilized for erythroid differentiation; however, current differentiation methods are insufficient to analyze globin proteins. In this study, we sought to improve erythroid differentiation from K562 cells to enable protein-level globin analysis. K562 cells were exposed to a variety of reagents including hemin, rapamycin, imatinib, and/or decitabine (known erythroid inducers), and cultured in basic culture media or erythropoietin-based differentiation media...
March 7, 2018: Experimental Hematology
Kamaleldin E Elagib, Ashton T Brock, Adam N Goldfarb
Fetal megakaryocytes (Mk) differ from adult Mk in key parameters that affect their capacity for platelet production. However, despite being smaller, more proliferative, and less polyploid, fetal Mk generally mature in the same manner as adult. The phenotypic features unique to fetal Mk predispose patients to several disease conditions: infantile thrombocytopenia, infantile megakaryoblastic leukemias, and poor platelet recovery after umbilical cord blood stem cell transplants. Ontogenic Mk differences also affect new strategies being developed to address global shortages of platelet transfusion units...
February 28, 2018: Experimental Hematology
Samik Upadhaya, Boris Reizis, Catherine M Sawai
The production of blood cells is dependent on the activity of a rare stem cell population that normally resides in the bone marrow (BM) of the organism. These hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate, ensuring this lifelong hematopoiesis. Determining the regulation of HSC functions should thus provide critical insight to advancing regenerative medicine. Until quite recently, HSCs were primarily studied using in vitro studies and transplantations into immunodeficient hosts...
February 28, 2018: Experimental Hematology
Blerta Green, Alberto Martin, Antoaneta Belcheva
C-Myc overexpression mediates lymphomagenesis, however, secondary genetic lesions are required for its full oncogenic potential. The origin and the mechanism of formation of these mutations are unclear. Using the lacI-mutation detection system, we show that secondary mutations occur early in B-cell development and are repaired by Msh2. The mutations at the lacI gene were predominantly at C:G base pairs and CpG motifs suggesting that they were formed due to cytosine deamination or oxidative damage of G. Hence, we investigated the role of Ogg1 and UNG glycosylases in c-Myc driven lymphomagenesis but found that their deficiencies did not influence the disease outcome in the Eµ c-Myc mouse model...
February 26, 2018: Experimental Hematology
Jana Mihalyova, Tomas Jelinek, Katerina Growkova, Matous Hrdinka, Michal Simicek, Roman Hajek
Inhibitors of anti-apoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. While non-selective agents have been limited by their affinity to different BCL2 members, and thus inducing excessive toxicity, the highly selective BCL2 inhibitor, venetoclax (ABT-199, Venclexta™), has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukaemia (CLL) with 17p deletion...
February 22, 2018: Experimental Hematology
Florence Zylbersztejn, Mario Flores-Violante, Thibault Voeltzel, Franck-Emmanuel Nicolini, Sylvain Lefort, Véronique Maguer-Satta
The microenvironment (niche) governs the fate of stem cells (SC) by balancing self-renewal and differentiation. Increasing evidence indicates that the tumor niche plays an active role in cancer but its (important) properties for tumor initiation progression and resistance remain to be identified. Clinical data show that leukemic stem cells (LSC) survival is responsible for disease persistence and drug resistance probably due to their sustained interactions with the tumor niche. The Bone Morphogenetic Protein (BMP) signaling is a key pathway controlling stem cells and their niche, such as BMP2 and BMP4 important in both normal and cancer context...
February 22, 2018: Experimental Hematology
Haiying Li, Chongyun Xing, Bin Zhou, Haige Ye, Jianhua Feng, Jianbo Wu, Shenmeng Gao
The aberrant overexpression of the Wilm's tumor-1 (WT1) in acute myeloid leukemia (AML) plays an important role in blast cell survival through enhancing proliferation and inhibiting apoptosis. However, the mechanism underlying the overexpression of WT1 remains unclear. Here, we identified miR-193a (miR-193a-5p) and miR-600 targeting and degrading WT1. MiR-193a and miR-600 synergistically reduced WT1 expression and suppressed the activity of a luciferase reporter through binding coding sequence (CDS) and 3'-untranslated regions (3'UTR) of WT1 mRNA, respectively...
February 13, 2018: Experimental Hematology
Kristin Fritsch, Sébastien Pigeot, Xiaomin Feng, Paul E Bourgine, Timm Schroeder, Ivan Martin, Markus G Manz, Hitoshi Takizawa
Hematopoietic stem cells (HSCs) are maintained in a specialized bone marrow (BM) environment, the so-called HSC niche, that provides pivotal factors for their maintenance. While the cellular and molecular components of the mouse BM HSC niche have been extensively studied using genetically modified animals, relatively little is known about the counterpart human BM niche components. We have previously shown with a developmental tissue engineering approach that human adult BM-derived mesenchymal stromal cells (MSCs) can develop into human bone organs (so-called ossicles) through endochondral ossification in vivo, and that these human ossicles are able to maintain functional mouse HSCs...
February 2, 2018: Experimental Hematology
Esther Tijchon, Liesbeth van Emst, Laurensia Yuniati, Dorette van Ingen Schenau, Mylène Gerritsen, Laurens T van der Meer, Owen Williams, Peter M Hoogerbrugge, Blanca Scheijen, Frank N van Leeuwen
Translocation t(12;21) (p13;q22), giving rise to the ETV6-RUNX1 fusion gene, is the most common genetic abnormality in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation usually arises in utero, but its expression is insufficient to induce leukemia and requires other cooperating genetic lesions for BCP-ALL to develop. Deletions affecting the transcriptional coregulator BTG1 are frequently observed in ETV6-RUNX1-positive leukemia. Here we show that Btg1 deficiency enhances the self-renewal capacity of ETV6-RUNX1 positive mouse fetal liver derived hematopoietic progenitors (FL-HPCs)...
February 2, 2018: Experimental Hematology
Betsabeh Khoramian Tusi, Merav Socolovsky
The advent of single cell transcriptomics has led to the proposal of a number of novel high- resolution models for the hematopoietic system. Testing the predictions generated by such models requires cell fate potential assays of matching, single cell resolution. Here we detail the development of an in vitro high throughput single-cell culture assay using flow-cytometrically-sorted single murine bone-marrow progenitors, that measures their differentiation into any of 5 myeloid lineages. We identify critical parameters for single cell culture outcome, including the choice of sorter nozzle size and pressure, culture media and the coating of culture dishes with extracellular matrix proteins...
January 30, 2018: Experimental Hematology
Lina Quan, Xiuwen Lan, Yuanyuan Meng, Xiuchen Guo, Yiwei Guo, Lina Zhao, Xue Chen, Aichun Liu
Immunotherapy has shown encouraging results in lymphoma. Pre-clinical and clinical trials have proven checkpoint blockade, such as PD-1 antibody, as an effective treatment for lymphoma, including diffuse large B-cell lymphoma (DLBCL). Combination of checkpoint blockades has emerged as a new way to treat lymphoma, however, the status of checkpoints expression and their function in DLBCL has not been fully elucidated yet. In this study, we examined the expression of BTLA, PD-1, TIM-3, LIGHT and LAG-3 in tumor micro-environmental T cells of DLBCL using flow cytometry, and compared the cytotoxicity and differentiation status of BTLA+ and BTLA- T-cells...
January 15, 2018: Experimental Hematology
Jian-Ming Gu, Shujun Yuan, Derek Sim, Keith Abe, Perry Liu, Martin Rosenbruch, Peter Bringmann, Katalin Kauser
Vaso-occlusive crisis (VOC) is the most common and debilitating complication of sickle cell disease (SCD); recurrent episodes cause organ damage and contribute to early mortality. Plasma placental growth factor (PlGF) levels are elevated in SCD and can further increase under hypoxic conditions in SCD mice. Treatment with a PlGF-neutralizing antibody (anti-PlGF Ab) in SCD mice reduced levels of monocyte chemoattractant protein-3, eotaxin, macrophage colony-stimulating factor, plasminogen activator inhibitor-1 significantly, and macrophage-derived chemokine and macrophage inflammatory protein-3β moderately; this may contribute to inhibition of leukocyte recruitment, activation, and thrombosis...
January 11, 2018: Experimental Hematology
Sachith Mettananda, Kevin Clark, Chris A Fisher, Jackie A Sloane-Stanley, Richard J Gibbons, Douglas R Higgs
In vitro erythroid differentiation systems are used to study the mechanisms underlying normal and abnormal erythropoiesis and to test the effects of various extracellular factors on erythropoiesis. The use of serum or conditioned medium in liquid cultures, and seeding cultures with heterogeneous peripheral blood mononuclear cells confound the reproducibility of these systems. Newer erythroid differentiation culture systems have overcome some of these limitations by using a fully defined, serum-free, medium and initiating cultures using purified CD34+ cells...
January 9, 2018: Experimental Hematology
Yuemin Gong, Mei Zhao, Wanzhu Yang, Ai Gao, Xiuxiu Yin, Linping Hu, Xiaofang Wang, Jing Xu, Sha Hao, Tao Cheng, Hui Cheng
Impaired production of healthy hematopoietic cells from residual hematopoietic stem cells (HSCs) leads to high mortality in acute myeloid leukemia (AML). Previous studies have identified p21 and Egr3 as intrinsic factors responsible for the growth arrest and differentiation blockade of normal HSCs in leukemia, however, the related extrinsic factors remains unknown. In this study, we demonstrated that TGFβ signaling was up-regulated in HSCs from MLL-AF9 induced AML mice bone marrow, due to excessive production of TGFβ1 especially from megakaryocytes, and over-activation of latent TGFβ1 protein...
January 4, 2018: Experimental Hematology
Yanhong Li, Shuai Zhu, Yuanyuan Zhang, Ting Liu, Linchong Su, Qiuping Zhang, Yubin Luo
The present study aims to investigate the influence of high fat diet (HFD) on hematopoietic system recovery under stress condition caused by 5-Fluouracil (5-Fu) and evaluate the alleviating benefit of PPAR-γ inhibition on aggravation of 5-Fu-induced toxicity under HFD condition. Survival rate of HFD or normal diet (ND) mice was monitored after 5-Fu injection. HSC and the progenitor cells in bone marrow were detected at various time points after 5-Fu administration by flow cytometry. Genes expression involved in stem cell and platelet proliferation were tested by RT-PCR...
January 3, 2018: Experimental Hematology
Ruosi Yao, Danyang Han, Xiaoyang Sun, Yu Xie, Qingyun Wu, Chunling Fu, Yao Yao, Hujun Li, Zhenyu Li, Kailin Xu
Multiple myeloma (MM) is an extremely serious plasma cell malignancy. Despite recent introduction of chemotherapies such as bortezomib and lenalidomide, it remains an incurable disease due to high rate of relapse and development of drug resistance. Epigenetic regulation is closely related with MM progression; nevertheless, the epigenetic modification mechanism of myeloma cell apoptosis has remained unclear. As a novel histone deacetylase inhibitor, Scriptaid's possible roles in MM progression have not been explored...
January 2, 2018: Experimental Hematology
Jeffrey L Kurkewich, Austin Boucher, Nathan Klopfenstein, Ramdas Baskar, Reuben Kapur, Richard Dahl
Mice deficient for microRNA (miRNA) cluster mirn23a exhibit increased B lymphopoiesis at the expense of myelopoiesis while hematopoietic stem and progenitor (HSPC) populations are unchanged. Mammals possess a paralogous mirn23b gene that can give rise to 3 mature miRNAs (miRs -23b, 24-1, and -27b) that have identical seed/ mRNA targeting sequences to their mirn23a counterparts. To assess whether compound deletion of mirn23a and mirn23b exacerbates the hematopoietic phenotype observed in mirn23a-/- mice, we generated a compound mirn23a-/-mirn23bfl/fl: Mx1-Cre conditional knockout mouse and assayed hematopoietic development after excision of mirn23b...
December 27, 2017: Experimental Hematology
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