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Experimental Hematology

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https://www.readbyqxmd.com/read/28527810/hif-1%C3%AE-stabilizing-agent-fg-4997-rescues-human-cd34-cell-mobilization-in-response-to-g-csf-in-immuno-deficient-mice
#1
Bianca Nowlan, Katarzyna Futrega, Marion E Brunck, Gail Walkinshaw, Lee E Flippin, Michael R Doran, Jean-Pierre Levesque
Granulocyte colony-stimulating factor (G-CSF) is routinely used in the clinic to mobilize hematopoietic stem progenitor cells (HSPC) into the patient's blood for collection and subsequent transplantation. However a significant proportion of patients who have previously received chemotherapy or radiotherapy and requiring autologous HSPC transplantation, cannot mobilize the minimal threshold of mobilized HSPC to achieve rapid and successful hematopoietic reconstitution. Although several alternatives to the G-CSF regime have been tested, few are in use in the clinic...
May 17, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28506695/d816v-mutation-in-the-kit-gene-activation-loop-has-a-greater-cell-proliferative-and-anti-apoptotic-ability-than-n822k-mutation-in-core-binding-factor-acute-myeloid-leukemia
#2
Ikuko Omori, Hiroki Yamaguchi, Koichi Miyake, Noriko Miyake, Tomoaki Kitano, Koiti Inokuchi
In core binding factor-acute myeloid leukemia (CBF-AML), there have been conflicting reports regarding the status as an unfavorable prognostic factor of mutation in the KIT gene, whose significance therefore remains unclear. We have reported previously that prognosis differs between the KIT D816V and N822K mutations. In the present study, we undertook an in vitro comparison of the cell-proliferative and anti-apoptotic ability of D816V and N822K. We transduced these KIT mutations into the IL-3-dependent cell line TF-1 (TF-1 KIT(D816V), TF-1 KIT(N822K))...
May 12, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28502830/with-me-or-against-me-tumour-suppressor-and-drug-resistance-activities-of-samhd1
#3
REVIEW
Nikolas Herold, Sean G Rudd, Kumar Sanjiv, Juliane Kutzner, Ida Hed Myrberg, Cynthia B J Paulin, Thale Kristin Olsen, Thomas Helleday, Jan-Inge Henter, Torsten Schaller
Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase that is involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits the permissivity of cells to infection with diverse viruses including human immunodeficiency virus (HIV-1) and controls endogenous retroviruses...
May 11, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28501597/reciprocal-regulation-between-hepcidin-and-erythropoiesis-and-its-therapeutic-application-in-erythroid-disorders
#4
REVIEW
Caiyi Wang, Zheng Fang, Zesen Zhu, Jing Liu, Huiyong Chen
Iron is required for hemoglobin production, and it plays a key role during erythropoiesis. Systemic iron homeostasis is mainly negatively regulated by the peptide hormone hepcidin, coded by the gene HAMP. Hepcidin excess may cause iron deficiency, iron-restricted erythropoiesis and anemia. Conversely, hepcidin insufficiency leads to iron overload and oxidative damage in multiple tissues. During regulation of hepcidin synthesis, multiple promoter elements in the HAMP gene respond to variable signaling pathways corresponding to different extracellular situations...
May 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28479420/cbp-catenin-antagonists-targeting-lsc-s-achilles-heel
#5
REVIEW
Yong-Mi Kim, EunJi Gang, Michael Kahn
Cancer Stem Cells (CSCs) including Leukemia Stem Cells (LSCs) exhibit self-renewal capacity and differentiation potential, and have the capacity to maintain or renew and propagate a tumor/leukemia. The initial isolation of CSCs/LSCs was in adult myelogenous leukemia, although more recently, the existence of CSCs in a wide variety of other cancers has been demonstrated. CSCs in general, and LSCs specifically in regards to this review, are responsible for initiation of disease, therapeutic resistance and ultimately disease relapse...
May 4, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28479419/novel-tumor-suppressor-function-of-klf4-in-pediatric-t-cell-acute-lymphoblastic-leukemia
#6
REVIEW
Ye Shen, Taylor J Chen, H Daniel Lacorazza
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients. Despite advances in the treatment of this disease, many children with T-cell ALL (T-ALL) die from disease relapse due to low responses to standard chemotherapy and the lack of a targeted therapy that selectively eradicates the chemoresistant leukemia-initiating cells (LICs) responsible for disease recurrence. We recently reported that the reprogramming factor KLF4 has tumor-suppressive function in children with T-ALL...
May 4, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28479418/development-of-an-assay-for-cellular-efflux-of-pharmaceutically-active-agents-and-its-relevance-to-understanding-drug-interactions
#7
Benigno C Valdez, Moustapha Hassan, Borje S Andersson
Drug interactions may dictate the failure or success of a treatment. Patients undergoing hematopoietic stem cell transplantation (HSCT) are exposed to various types of drugs and it is of utmost importance to understand how these drugs interact. The pharmacokinetics of busulfan, melphalan and cyclophosphamide, commonly used drugs in HSCT, are known to be affected by a variety of drugs with differing molecular structures. We hypothesized that these structurally-unrelated drugs affect the transport of DNA alkylating agents...
May 4, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28457753/expression-of-cd25-on-leukemic-stem-cells-in-bcr-abl1-cml-potential-diagnostic-value-and-functional-implications
#8
REVIEW
Irina Sadovnik, Harald Herrmann, Gregor Eisenwort, Katharina Blatt, Gregor Hoermann, Niklas Mueller, Wolfgang R Sperr, Peter Valent
Chronic myeloid leukemia (CML) is a stem cell-derived leukemia in which neoplastic cells exhibit the Philadelphia (Ph) chromosome and the related oncoprotein, BCR-ABL1. The disease is characterized by an accumulation of myeloid precursor cells in the peripheral blood (PB) and bone marrow (BM). A small fraction of neoplastic cells in the CML clone supposedly exhibits self-renewal and thus long-term disease-propagating ability. However, so far, little is known about the phenotype, function, and target expression-profiles of these leukemic stem cells (LSC)...
April 27, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28456748/reprogramming-acute-myeloid-leukemia-into-sensitivity-for-retinoic-acid-driven-differentiation
#9
REVIEW
Noortje van Gils, Han J M P Verhagen, Linda Smit
The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale to use retinoic acid-based therapy also for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may efficiently drive leukemic cells into differentiation and/or apoptosis in a subset of AML patients with a NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Since not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have been very disappointing, the identification of additional biomarkers may help to identify patients that strongly respond to ATRA-based therapy...
April 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28456747/blos2-maintains-hematopoietic-stem-cells-in-the-fetal-liver-via-repressing-notch-signaling
#10
REVIEW
Qiuping He, Suwei Gao, Junhua Lv, Wei Li, Feng Liu
During development, hematopoietic stem cells (HSCs) undergo a rapid expansion in the fetal liver (FL) after their emergence in the aorta-gonad-mesonephros (AGM) region. We recently reported that the endolysosomal trafficking factor BLOS2, encoded by the Bloc1s2 gene, regulates HSPC emergence in the AGM region; however, whether it plays a role in the FL remains unknown. Here, we show that BLOS2 plays an essential role in regulation of HSC proliferation and differentiation in the FL. Bloc1s2 depletion leads to elevated Notch signaling, with an increased frequency but weaken self-renewal ability of FL HSCs...
April 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28456746/genetically-engineered-mesenchymal-stromal-cells-producing-il3-and-tpo-to-further-improve-human-scaffold-based-xenograft-models
#11
M Carretta, B de Boer, J Jaques, A Antonelli, S J Horton, H Yuan, J D de Bruijn, R W J Groen, E Vellenga, J J Schuringa
Recently, NOD-SCID IL2Rγ(-/-) (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or matrigel in order to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties [1-3]. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human IL3 and TPO...
April 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28450163/murine-hemogenic-endothelial-precursors-display-heterogeneous-hematopoietic-potential-ex-vivo
#12
Miguel Ganuza, Brandon Hadland, Ashley Chabot, Chen Li, Guolian Kang, Irwin Bernstein, Shannon McKinney-Freeman
Hematopoietic Stem and Progenitor Cells (HSPCs) sustain life-long hematopoiesis and are first detected in the embryo by transplantation at embryonic day 10.5. (E10.5). HSPCs are mesodermal in origin and ultimately emerge from a subset of arterial endothelium (i.e. hemogenic endothelium), which is highly concentrated in the aorta-gonad-mesonephros region (AGM) of the mid-gestation embryo. Here, we employ clonal ex vivo assays in which endothelial cells isolated from the mid-gestation aorta and vitelline and umbilical arteries are co-cultured on supportive stroma to show that only about 0...
April 24, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28435024/lkb1-deletion-in-murine-b-lymphocytes-promotes-cell-death-and-cancer
#13
George P Souroullas, Yuri Fedoriw, Louis M Staudt, Norman E Sharpless
LKB1 (aka STK11) is a potent tumor suppressor in solid tumors such as melanoma and lung adenocarcinoma, but inactivation in hematopoietic cells causes cell death, without signs of tumorigenesis. We noted somatic LKB1 deletion or mutation at low frequency in human B cell lymphoma. In order to determine if LKB1 inactivation is a passenger or driver event in lymphoid cancers, we examined the effects of conditional inactivation of Lkb1 in murine lymphocytes. Consistent with prior reports, Lkb1 deletion in either T or B cells resulted in massive, lineage-specific apoptosis...
April 20, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28433605/stability-of-patient-specific-features-of-altered-dna-replication-timing-in-xenografts-of-primary-human-acute-lymphoblastic-leukemia
#14
Takayo Sasaki, Juan Carlos Rivera-Mulia, Daniel Vera, Jared Zimmerman, Sunny Das, Michelle Padget, Naoto Nakamichi, Bill H Chang, Jeff Tyner, Brian J Druker, Andrew P Weng, Curt I Civin, Connie J Eaves, David M Gilbert
Genome-wide DNA replication timing (RT) profiles reflect the global 3D chromosome architecture of cells. They also provide a comprehensive and unique megabase-scale picture of the cellular epigenetic state. Thus normal differentiation involves reproducible changes in RT and transformation generally perturbs these, although the potential effects of altered RT on the properties of transformed cells remain largely unknown. A major challenge to interrogating these issues in human acute lymphoid leukemia (ALL) is the low proliferative activity of most of the cells, which may be further reduced in cryopreserved samples and difficult to overcome in vitro...
April 19, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28412288/adult-t-type-lymphoblastic-lymphoma-treatment-advances-and-prognostic-indicators
#15
REVIEW
Stéphane Lepretre, Carlos Graux, Aurore Touzart, Elizabeth Macintyre, Nicolas Boissel
T-cell lymphoblastic lymphoma (T-LBL) is a rare, aggressive neoplasm of precursor T cells that occurs mostly in adolescents and young adults. In this review, we describe the treatment of adult T-LBL with a focus on recent advances using pediatric-inspired acute lymphoblastic leukemia regimens, which have greatly improved outcome. We also discuss the development of prognostic indicators for T-LBL, especially oncogenetic factors, that can identify patients at higher risk of relapse and should help further extend T-LBL patient survival...
April 12, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28410882/epo-reprograms-the-epigenome-of-erythroid-cells
#16
Andrea A Perreault, Mary Lauren Benton, Mark J Koury, Stephen J Brandt, Bryan J Venters
The hormone erythropoietin (Epo) is required for erythropoiesis, yet its molecular mechanism of action remains poorly understood, particularly in regards to chromatin dynamics. To investigate how Epo modulates the erythroid epigenome, we performed epigenetic profiling using an ex vivo murine cell system that undergoes synchronous erythroid maturation in response to Epo stimulation. Our findings define the repertoire of Epo-modulated enhancers, illuminating a new facet of Epo signaling. First, a large number of enhancers rapidly responded to Epo stimulation, revealing a cis-regulatory network of Epo-responsive enhancers...
April 11, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28408238/novel-roles-for-podocalyxin-in-regulating-stress-myelopoiesis-rap1a-and-neutrophil-migration
#17
Pan Li, Aldona A Karaczyn, Rose McGlauflin, Amanda J Favreau-Lessard, Edward Jachimowicz, Calvin P Vary, Kailin Xu, Don M Wojchowski, Pradeep Sathyanarayana
Podocalyxin (Podxl) is a CD34 orthologue and cell surface sialomucin reported to have roles in renal podocyte diaphragm slit development; vascular cell integrity; and the progression of blood, breast, and prostate cancers. Roles for Podxl during nonmalignant hematopoiesis, however, are largely undefined. We have developed a Vav-Cre Podxl knockout (KO) mouse model, and report on novel roles for Podxl in governing stress myelopoiesis. At steady state, Podxl expression among hematopoietic progenitor cells was low level but was induced by granulocyte colony-stimulating factor (G-CSF) in myeloid progenitors and by thrombopoietin in human stem cells...
April 10, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28390857/targeted-deletion-of-the-hoxa-cluster-affects-b-lymphopoiesis-through-depletion-of-early-lymphoid-progenitors
#18
Charles-Étienne Lebert-Ghali, Alexander Thompson, Heather J Melichar, Janet J Bijl
It is well established that Hoxa genes play a critical role in the proliferative capacity of adult hematopoietic stem and progenitor cells, but the importance of Hoxa genes in later stages of hematopoietic differentiation is less clear. Previously, we observed that B-cell numbers were reduced in adult mice in which Hoxa deletion was induced. In the current study, we investigated the requirement of Hoxa genes at different stages of B-cell development. Using an MxCre-inducible conditional knock-out mouse model, we showed that immature B-cell fractions and early lymphoid progenitors were markedly reduced in the absence of Hoxa, whereas mature B-cell populations were found at levels comparable to controls...
April 5, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28342808/role-of-mtorc1-s6k1-signaling-pathway-in-regulation-of-hematopoietic-stem-cell-and-acute-myeloid-leukemia
#19
REVIEW
Joydeep Ghosh, Reuben Kapur
Dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1)-p70 ribosomal protein kinase 1 (S6K1) signaling pathway occurs frequently in acute myeloid leukemia (AML) patients. This pathway also plays a critical role in maintaining normal cellular processes. Given the importance of leukemia stem cells (LSCs) in the development of minimal residual disease, it is critical to use therapeutic interventions that target the LSC population to prevent disease relapse. The mTORC1-S6K1 pathway has been identified as an important regulator of hematopoietic stem cell (HSC) and LSC functions...
March 22, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28315701/perspective-a-defined-role-for-multiple-fanconi-anemia-gene-products-in-dna-damage-associated-ubiquitination
#20
REVIEW
Winnie Tan, Andrew J Deans
Fanconi anemia (FA) is an inherited blood disorder that causes bone marrow failure and high predisposition to cancers. The FA pathway guards the cell's genome stability by orchestrating the repair of interstrand cross-linking during the S phase of the cell cycle, preventing the chromosomal instability that is a key event in bone marrow failure syndrome. Central to the FA pathway is loss of monoubiquitinated forms of the Fanconi proteins FANCI and FANCD2, a process that is normally mediated by a "core complex" of seven other Fanconi proteins...
March 16, 2017: Experimental Hematology
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