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Experimental Hematology

Susumu Goyama, Janet Schibler, James C Mulloy
Transcription factor RUNX1 plays a crucial role in hematopoiesis, and its activity is tightly regulated at both transcriptional and post-translational levels. However, translational control of RUNX1 expression has not been fully understood. In this study, we demonstrated that RUNX1b mRNA is translated from two alternative initiation sites (Met-1 and Met-25), giving full-length RUNX1b and a shorter protein lacking the first 24 amino acids (RUNX1ΔN24). Presence/absence of strong Kozak consensus sequences around Met-1 determines which initiation site is mainly used in RUNX1b cDNA...
January 25, 2019: Experimental Hematology
Kristin Fritsch, Sébastien Pigeot, Xiaomin Feng, Paul E Bourgine, Timm Schroeder, Ivan Martin, Markus G Manz, Hitoshi Takizawa
No abstract text is available yet for this article.
January 25, 2019: Experimental Hematology
Peter Karagiannis, Shinya Yamanaka, Megumu K Saito
Primary immunodeficiency diseases (PIDs) are a heterogeneous group of rare immune disorders with genetic causes. Effective treatments using hematopoietic stem cells or pharmaceutical agents have been around for decades. However, for many patients, these treatment options are ineffective, partly because the rarity of these PIDs complicates the diagnosis and therapy. Induced pluripotent stem cells (iPSCs) offer a potential solution to these problems. The proliferative capacity of iPSCs allows for the preparation of a large, stable supply of hematopoietic cells with the same genome as the patient, allowing for new human cell models that can trace cellular abnormalities during the pathogenesis and lead to new drug discovery...
January 19, 2019: Experimental Hematology
Mahmoud I Elbadry, J Luis Espinoza, Shinji Nakao
The plasticity of induced pluripotent stem cells (iPSCs) with the potential to differentiate into virtually any type of cells and the feasibility of generating hematopoietic stem progenitor cells (HSPCs) from patient-derived iPSCs (iPSC-HSPC) has many potential applications in hematology. For example, iPSC-HSPCs are being used for leukemogenesis studies, and the application of iPSC-HSPCs in various cell replacement therapies is being evaluated. The use of iPSC-HSPCs can now provide an invaluable resource for the study of diseases associated with the destruction of HSPCs, such as bone marrow failure syndromes (BMFSs)...
January 18, 2019: Experimental Hematology
Ali G Turhan, A Foudi, J W Hwang, C Desterke, F Griscelli, A Bennaceur-Griscelli
Over the last decade, the possibility of reprogramming malignant cells to a pluripotent state has been achieved in several hematological malignancies, including myeloproliferative neoplasms, myelodysplastic syndromes, and chronic myeloid leukemia (CML). It has been shown that it is readily possible to generate induced pluripotent stem cells (iPSCs) from several types of primary CML cells and to generate progenitors and differentiated cells with variable efficiency. Although these experiments have brought some new insights in the understanding of CML pathophysiology, the ultimate goal of generating induced leukemic stem cells (LSCs) with long-term multilineage potential has not yet been demonstrated...
January 16, 2019: Experimental Hematology
Mark P Chao, Ravindra Majeti
The ability to epigenetically reprogram differentiated somatic cells to pluripotency, the discovery of induced pluripotent stem cells (iPSCs), has unlocked fundamental biologic insights into numerous genetic diseases. These insights have resulted from the key property of iPSCs to differentiate into all cell lineages in an unlimited manner while maintaining the genetic identity of the originating cell. iPSCs have been utilized to investigate both monogenic and complex genetic disorders spanning hereditary and acquired diseases...
January 16, 2019: Experimental Hematology
Chong Yang, Michihiro Hashimoto, Quy Xiao Xuan Lin, Darren Qiancheng Tan, Toshio Suda
Erythropoiesis is a highly-coordinated stepwise process involving the progressive clearance of mitochondria via mitophagy. Based on the expression of several macroautophagy and mitophagy specific genes, we identified a sequential changes in the transcriptional pattern during terminal erythroid differentiation. Since erythroid cells are a major source of serum sphingosine-1-phosphate, we analysed the role of sphingolipid signaling in erythropoiesis and demonstrate that sphingosine kinase activity promotes terminal erythroid differentiation by regulating the expression of key mitophagy genes Pink1 and Bnip3l/Nix...
January 15, 2019: Experimental Hematology
Yun Hsiao Lin, Michael Forster, Yue Liang, Mansen Yu, HanChen Wang, Francis Robert, David Langlais, Jerry Pelletier, Simon Clare, Anastasia Nijnik
Ubiquitin specific protease 44 (USP44) is a nuclear protein with deubiquitinase (DUB) catalytic activity, implicated as an important regulator of cell cycle progression, gene expression, and genomic stability. Dysregulation in the molecular machinery controlling cell proliferation, gene expression, and genomic stability in human or mouse is commonly linked to hematopoietic dysfunction, immunodeficiency, and cancer. We therefore set to explore the role of USP44 in hematopoietic and immune systems, through characterization of a Usp44-deficient mouse model...
January 9, 2019: Experimental Hematology
Benjamin Dannenmann, Azadeh Zahabi, Perihan Mir, Benedikt Oswald, Regine Bernhard, Maksim Klimiankou, Tatsuya Morishima, Cornelia Zeidler, Lothar Kanz, Nico Lachmann, Thomas Moritz, Karl Welte, Julia Skokowa
We describe the establishment of an embryoid body (EB)-based protocol for hematopoietic/myeloid differentiation of human induced pluripotent stem cells (iPSCs) that allows the generation of CD34+ cells or mature myeloid cells in vitro. Using this model, we were able to recapitulate the defective granulocytic differentiation in patients with severe congenital neutropenia (CN), an inherited pre-leukemia bone marrow failure syndrome. Importantly, in vitro maturation arrest of granulopoiesis was associated with an elevated unfolded protein response (UPR) and enhanced expression of the cell cycle inhibitor p21...
January 4, 2019: Experimental Hematology
Davide Bernarreggi, Somayeh Pouyanfard, Dan S Kaufman
Mouse and human pluripotent stem cells have been widely used to study the development of the hematopoietic and immune systems. Although not all cells can be derived with the same efficiency, immune cells such as natural killer (NK) cells and macrophages can be easily produced from PSCs to enable development of new cell-based therapies. NK cells and macrophages are part of the innate immune system, the first line of defense against malignancies and infectious disease. Human embryonic stem cell (hESC)- and induced pluripotent stem cell (iPSC)-derived NK cells can be produced at a clinical scale suitable for translation into clinical trials...
January 4, 2019: Experimental Hematology
Damir Simic, Nianli Sang
Histone deacetylase inhibitors (HDACi) have demonstrated effectiveness against lymphomas and myelomas in clinical practice. However, common to all currently approved broad acting HDACi (panHDACi) is dose limiting thrombocytopenia, which has prevented wider use in cancer therapy. Using CD34+ hematopoietic stem cells (HSC), here we show megakaryocyte (MK) cell maturation/differentiation is impaired by broad acting (pan) HDACi, correlating to clinical thrombocytopenia. Importantly, we demonstrate that inhibitors of class II HDACs including LMK235 and tubacin at clinically relevant concentrations do not affect megakaryocyte maturation...
January 3, 2019: Experimental Hematology
Thierry Guillaume, Virginie Dehame, Patrice Chevallier, Pierre Peterlin, Alice Garnier, Marc Grégoire, Edward Pichinuk, Daniel B Rubinstein, Daniel H Wreschner
Cell surface molecules aberrantly expressed or overexpressed by myeloid leukemic cells represent potential disease-specific therapeutic targets for antibodies. MUC1 is a polymorphic glycoprotein whose cleavage yields two unequal chains: a large extracellular α subunit containing a tandem repeat array bound in a strong non-covalent interaction to a smaller β subunit containing the transmembrane and cytoplasmic domains. Because the α chain can be released from the cell-bound domains of MUC1, agents directed against the α chain will not effectively target MUC1+ cells...
December 26, 2018: Experimental Hematology
Huichun Zhan, Kenneth Kaushansky
The role of stem cells in normal and neoplastic hematopoiesis is well established. However, neither normal nor neoplastic hematopoietic stem cells (HSCs) develop in isolation, and accumulating evidence indicates that a critical developmental role is played by the perivascular "niche". The cellular, humoral and cell surface contacts that provide the proper environment for HSC survival, proliferation and differentiation are becoming increasingly better understood. A number of studies have established that endothelial cells (ECs), several types of perivascular stromal cells and megakaryocytes (MKs) provide several cell surface and secreted molecules required for HSC development...
December 26, 2018: Experimental Hematology
Amélie Montel-Hagen, Gay M Crooks
The generation of T cells from human pluripotent stem cells (PSCs) opens a valuable experimental window into developmental hematopoiesis and raises the possibility of a new therapeutic approach for T cell immunotherapy. After directing PSC through mesoderm and early hematopoietic developmental stages, commitment to the T cell lineage has been achieved by several groups using co-culture with stromal cells that express a notch-ligand, recapitulating the critical signals that initiate the first stages of normal T cell differentiation in the thymus...
December 24, 2018: Experimental Hematology
Stefan Radtke, Yan-Yi Chan, Trisha R Sippel, Hans-Peter Kiem, Anthony Rongvaux
Pre-clinical feasibility, safety, and efficacy testing of hematopoietic stem cell (HSC)-mediated gene therapy approaches is commonly performed in large animal models such as nonhuman primates (NHPs). Here we wished to determine whether mouse models would allow engraftment of NHP HSPCs which would enable more facile and less costly evaluation of promising strategies. In this study, we comprehensively tested two mouse strains for the engraftment of NHP CD34+ hematopoietic stem and progenitor cells. No engraftment of NHP HSPCs was observed in NSG mice, whereas the humanized MISTRG model did demonstrate dose-dependent multilineage engraftment of NHP cells in the peripheral blood, bone marrow, spleen, and thymus...
December 24, 2018: Experimental Hematology
Tianjiao Wang, Brandi Glover, Gayla Hadwiger, Christopher A Miller, Orsola di Martino, John S Welch
SMC3 encodes a subunit of the cohesin complex that has canonical roles in regulating sister chromatids segregation during mitosis and meiosis. Recurrent heterozygous mutations in SMC3 have been reported in acute myeloid leukemia (AML) and other myeloid malignancies. In this study, we investigated whether the missense mutations in SMC3 might have dominant-negative effects or phenocopy loss-of-function effects by comparing the consequences of Smc3 deficient and haploinsufficient mouse models. We found that homozygous deletion of Smc3 during embryogenesis or in adult mice led to hematopoietic failure, suggesting that SMC3 missense mutations are unlikely to be associated with simple dominant negative phenotypes...
December 13, 2018: Experimental Hematology
Igor I Slukvin, Gene I Uenishi
Human pluripotent stem cells (hPSCs) have been suggested as a potential source for the de novo production of blood cells for transfusion, immunotherapies and transplantation. However, even with advanced hematopoietic differentiation methods, the primitive and myeloid-restricted waves of hematopoiesis dominate in hPSC differentiation cultures while cell-surface markers to distinguish these waves of hematopoiesis from lympho-myeloid hematopoiesis remain unknown. In the embryo, hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries, but not veins...
November 27, 2018: Experimental Hematology
Eirini P Papapetrou
Modeling human diseases with patient-derived induced pluripotent stem cells (iPSCs) offers unique research opportunities and is particularly attractive for hematology research. Whereas monogenic inherited blood diseases featured prominently among the first proof-of-principle studies of iPSC modeling, malignant hematologic disorders have been off to a slower start due to challenges in the derivation of iPSCs from cancer cells and the need to establish robust differentiation protocols and standardize phenotypic assays of iPSC-derived hematopoiesis...
November 24, 2018: Experimental Hematology
Zhijie Wu, Valentina Giudice, Jichun Chen, Wanling Sun, Zenghua Lin, Keyvan Keyvanfar, Nidhi Talasani, Sachiko Kajigaya, Xingmin Feng, Neal S Young
Interleukin-18 (IL-18), also known as interferon-gamma (IFN-γ)-inducing factor, is involved in Th1 responses and regulation of immunity. Accumulating evidence implicates IL-18 in autoimmune diseases, but little is known of its role in acquired aplastic anemia (AA), the immune-mediated destruction of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). IL-18 protein levels were significantly elevated in sera of severe AA (SAA) patients, including both responders and nonresponders assayed before treatment, and decreased after treatment...
January 2019: Experimental Hematology
Yusuke Isshiki, Atsushi Iwama
Polycomb group (PcG) proteins are the key epigenetic regulators of normal hematopoiesis and the dysregulation of their functions is closely involved in the pathogenesis of hematological malignancies. These proteins function in the multimeric complexes called polycomb repressive complex (PRC) 1 and 2. In addition to canonical PRC1, four noncanonical PRC1 complexes have been identified. In contrast to canonical PRC1, which is recruited to its target sites in a manner dependent on H3K27me3, noncanonical PRC1 complexes are recruited to their target sites independently of H3K27me3...
December 2018: Experimental Hematology
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