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Experimental Hematology

Seerat Elahi, Shawn M Egan, G Aaron Holling, Rachel L Kandefer, Michael J Nemeth, Scott H Olejniczak
Recent biochemical characterization of Arsenic resistance protein 2 (Ars2) has established it as central to determining the fate of nascent RNA polymerase II (RNAPII) transcripts. Through interactions with the nuclear 5'-7-methylguanosine (7mG) cap binding complex (CBC), Ars2 promotes co-transcriptional processing coupled with nuclear export or degradation of several classes of RNAPII transcripts, allowing for gene expression programs that facilitate rapid and sustained proliferation of immortalized cells in culture...
May 15, 2018: Experimental Hematology
Evert-Jan F M de Kruijf, Rob Zuijderduijn, Marjolein C Stip, Willem E Fibbe, Melissa van Pel
Mesenchymal stromal cells (MSC) support hematopoietic stem cells (HSC) in vivo and enhance HSC engraftment and hematopoietic recovery upon co-transplantation with HSC. These data have led to the hypothesis that MSC may impact the HSC niche, leading to changes in HSC retention and trafficking. We studied the effect of MSC administration on the HSC compartment in the bone marrow (BM) in mice. Following injection of MSC, HSC numbers in the BM were decreased coinciding with an increased cell cycle activity compared to PBS-injected controls...
May 15, 2018: Experimental Hematology
Xiangguo Shi, Ayumi Kitano, Yajian Jiang, Victor Luu, Kevin A Hoegenauer, Daisuke Nakada
Recent advances in next-generation sequencing have identified novel mutations and revealed complex genetic architectures in human hematological malignancies. Moving forward, new methods to quickly generate animal models that recapitulate the complex genetics of human hematological disorders are needed to transform the genetic information to new therapies. Here, we used a ribonucleoprotein-based CRISPR/Cas9 system to model human clonal hematopoiesis of indeterminate potential and acute myeloid leukemia (AML)...
May 8, 2018: Experimental Hematology
Catherine E Jenkins, Samuel Gusscott, Rachel J Wong, Olena O Shevchuk, Gurneet Rana, Vincenzo Giambra, Kateryna Tyshchenko, Rashedul Islam, Martin Hirst, Andrew P Weng
RUNX1 is frequently mutated in T-cell acute lymphoblastic leukemia (T-ALL). The spectrum of RUNX1 mutations has led to the notion that it acts as a tumor suppressor in this context; however, other studies have placed RUNX1 along with transcription factors TAL1 and NOTCH1 as core drivers of an oncogenic transcriptional program. To reconcile these divergent roles, we knocked down RUNX1 in human T-ALL cell lines and deleted Runx1 or Cbfb in primary mouse T-cell leukemias. RUNX1 depletion consistently resulted in reduced cell proliferation and increased apoptosis...
May 4, 2018: Experimental Hematology
Christophe Desterke, Maud Voldoire, Marie-Laure Bonnet, Nathalie Sorel, Sarah Pagliaro, Hind Rahban, Annelise Bennaceur Griscelli, Emilie Cayssials, Jean-Claude Chomel, Ali G Turhan
The BCR-ABL oncogene, hallmark of chronic myeloid leukemia (CML), has been shown to activate several signaling pathways in leukemic cells. The natural history of this disease has been radically modified by tyrosine kinase inhibitors (TKIs). However, resistance to several lines of TKI therapies and progression to blast crisis (BC) remain significant concerns. In order to identify novel signaling pathways induced by BCR-ABL, we performed a transcriptome analysis in BCR-ABL-expressing UT-7 cell line. More than 2000 genes differentially expressed between BCR-ABL-expressing and parental UT-7 cells were identified, and ETS1 was found to be the most up-regulated...
May 4, 2018: Experimental Hematology
Sha Si, Yaeko Nakajima-Takagi, Takahito Iga, Mayoko Tsuji, Libo Hou, Motohiko Oshima, Shuhei Koide, Atsunori Saraya, Satoshi Yamazaki, Keiyo Takubo, Yoshiaki Kubota, Tohru Minamino, Atsushi Iwama
Hematopoietic stem cells (HSCs) are exposed to various insults, such as genotoxic stress, inflammation, and infection, which directly affect HSCs. These insults deplete HSCs, cause a functional decline in HSCs, and promote their aging and transformation. However, the impact of hematopoietic insults on niche cells remains largely unknown. We have previously reported that p53 is activated in blood vessels by various stresses, including hypoxia, inflammation, and aging, and contributes to tissue dysfunction and metabolic abnormalities...
April 27, 2018: Experimental Hematology
Lauren A Thurgood, Karen M Lower, Cindy Macardle, Bryone J Kuss
The cryopreservation of peripheral blood mononuclear cells (PBMCs) is a routine research laboratory process, enabling long-term storage of primary patient blood samples. Retrospective analysis of these samples has the potential to identify markers which may associate with prognosis and response to treatment. In order to draw valid biological conclusions from this type of analysis, it is essential to ensure that any observed changes are directly related to the pathology of the disease rather than the preservation process itself...
April 26, 2018: Experimental Hematology
Adam C Wilkinson, Maiko Morita, Hiromitsu Nakauchi, Satoshi Yamazaki
Hematopoietic stem cells (HSCs) are used clinically in bone marrow transplantation due to their unique ability to reform the entire hematopoietic system. We recently reported that HSCs are highly sensitive to valine, one of the three branched-chain amino acids (BCAAs) along with isoleucine and leucine. Dietary depletion of valine could even be used as a conditioning regimen for HSC transplantation. Here, we report that HSCs are highly sensitive to the balance of BCAAs, with both proliferation and survival reduced by BCAA imbalance...
April 26, 2018: Experimental Hematology
David Azoulay, Yair Herishanu, Mika Shapiro, Yarden Brenshaft, Celia Suriu, Luiza Akria, Andrei Braester
Increased CXCR4 expression is related to unfavorable disease in chronic lymphocytic leukemia (CLL). Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that has previously been shown to interact with CXCR4 in neuronal cells. In this report we studied the in vitro effect of BDNF on CXCR4 expression and chemotaxis towards SDF-1 in freshly isolated CLL cells. We also explored correlations between serum BDNF levels in CLL patients and the disease characteristics and clinical course. Incubation of CLL cells with recombinant BDNF (50 ng/ml) resulted in a downregulation of CXCR4 surface expression and atenuated chemotaxis towards SDF1...
April 26, 2018: Experimental Hematology
Victoria J Weston, Wenbin Wei, Tatjana Stankovic, Pamela Kearns
Heterogeneous upregulation of multiple pro-survival pathways underlies resistance to damage-induced apoptosis in acute lymphoblastic leukaemia (ALL) cells despite normal p53 responses. Here we identify the dual combination of IGF1/R and MEK inhibition using AG1024 and U0126 can sensitise apoptosis-resistant ALL cells to ionising radiation (IR)-induced DNA damage irrespective of effect of single pathway inhibition in vitro. This AG1024+U0126 combination also significantly potentiates the ability of the core chemotherapy compounds vincristine, dexamethasone and daunorubicin to kill ALL cells in vitro...
April 12, 2018: Experimental Hematology
Yasmine Ouzegdouh, Claude Capro N, Thomas Bauer, Etienne Puymirat, Jean-Luc Diehl, John F Martin, Elisabeth Cramer-Bord É
Animal evidence that platelet production occurs in the lungs is growing [1]. We have investigated whether there is evidence to support pulmonary platelet production from studies using human conditions. We documented the presence of MK in the human pulmonary circulation and analysed the role of the vascular microenvironment on MK function. Our results suggest that the endothelial microenvironment favors platelet formation and that von Willebrand factor combined with appropriate physical forces in flowing blood are determinant for platelet release...
April 11, 2018: Experimental Hematology
Ashley A Newcombe, Brenda E S Gibson, Karen Keeshan
There is a desperate need for new and effective therapeutic approaches for AML in both children and adults. Epigenetic aberrations are common in adult AML, and many novel epigenetic compounds are in clinical development that may improve patient outcomes. Mutations in epigenetic regulators occur less frequently in AML in children compared to adults. However, investigating the potential benefits of epigenetic therapy in paediatric AML is an important issue that will be discussed in this review.
March 30, 2018: Experimental Hematology
Niraja M Dighe, Kang Wei Tan, Lay Geok Tan, Steven S W Shaw, Suzanne M K Buckley, Dedy Sandikin, Nuryanti Johana, Yi-Wan Tan, Arijit Biswas, Mahesh Choolani, Simon N Waddington, Michael N Antoniou, Jerry K Y Chan, Citra N Z Mattar
Major haemoglobinopathies place tremendous strain on global resources. Intrauterine haemopoietic cell (IUHCT) and gene (IUGT) therapies can potentially reduce perinatal morbidities with greater efficacy than postnatal therapy alone. We performed both procedures in the thalassaemic HbbTh3/+ murine model. Intraperitoneal delivery of coisogenic cells at E13-14 produced dose-dependent chimerism. High-dose adult bone marrow (BM) cells maintained 0.2-3.1% chimerism over ~24 weeks and treated heterozygotes demonstrated higher chimerism than wild-type pups (1...
March 29, 2018: Experimental Hematology
Nisha Narayan, Cameron P Bracken, Paul G Ekert
Acute myeloid leukemia (AML) arises when immature myeloid blast cells acquire multiple, recurrent genetic and epigenetic changes that results in dysregulated proliferation. Acute leukemia is the most common form of paediatric cancer, with AML accounting for ~20% of all leukemias in children. The genomic aberrations that drive AML inhibit myeloid differentiation and activate signal transduction pathways that drive proliferation. MicroRNAs, a class of small (~22 nucleotide) non-coding RNA that post-transcriptionally suppress the expression of specifically targeted transcripts, are also frequently dysregulated in AML which may prove useful for the purposes of disease classification, prognosis and future therapeutic approaches...
March 27, 2018: Experimental Hematology
Yihong Li, Dun Liu, Xinhua Zhang, Zhiming Li, Yuhua Ye, Qifa Liu, Jie Shen, Zhi Chen, Huajie Huang, Yunhao Liang, Xu Han, Jing Liu, Xiuli An, Narla Mohandas, Xiangmin Xu
Haplo-insufficiency of Erythroid Krüppel-like factor (EKLF/KLF1) has recently been shown to ameliorate the clinical severity of β-thalassemia by increased expression levels of fetal hemoglobin (HbF). The underlying mechanisms for role of EKLF in regulating HbF are of great interest but remain incompletely understood. In this study, we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in EKLF regulation and to validate the role of miR-326 in HbF modification. We found that miR-326 directly suppresses EKLF expression by targeting its 3' untranslated region (3'UTR)...
March 27, 2018: Experimental Hematology
Sayantani Sinha, Shankha Subhra Chatterjee, Mayukh Biswas, Arijit Nag, Debasis Banerjee, Rajib De, Amitava Sengupta
Acquired aplastic anemia (AA) is a bone marrow failure that is associated with auto-immune destruction of hematopoietic stem cells (HSCs). Although somatic mutations have been identified in AA patients, mutations alone would not suffice understanding AA pathophysiology. SWI/SNF is an evolutionarily conserved, multi-subunit, ATP-dependent chromatin remodeling protein complex that plays important role in mammalian hematopoiesis. Herein, gene expression analysis identified a significant loss of SWI/SNF core component SMARCC1 along with ARID1B, ACTL6A and SMARCD1 in human AA bone marrow CD34+ HSC and progenitors (HSPCs) compared to normal HSPCs...
March 26, 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 (DLIs) 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, 46 patients were included in the study; 30 (65%) had acute myeloid leukemia and 16 (35%) had acute lymphoblastic leukemia. The median age was 38 years (range 4-66)...
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
Although 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 knockout [KO]) lymph node (LN) cells into minor-antigen mismatched mice resulted in early mortality, as well as more severe bone marrow (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 a basic culture medium or erythropoietin-based differentiation medium...
March 7, 2018: Experimental Hematology
Stephen Capone, Kwasi M Connor, Anthony Colombo, Xin Li, Tim J Triche, Giridharan Ramsingh
Genomic transposable elements (TEs) constitute the 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. Recently, we showed that the expression of TEs is suppressed along with immune pathways in leukemic stem cells (LSCs) in acute myeloid leukemia, suggesting a potential mechanism for immune escape of LSCs. This indicated that, during oncogenesis, where there is escape from senescence, expression of TEs is suppressed...
June 2018: Experimental Hematology
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