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Experimental Hematology

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https://www.readbyqxmd.com/read/28652130/tal1-as-a-master-oncogenic-transcription-factor-in-t-cell-acute-lymphoblastic-leukemia
#1
REVIEW
Takaomi Sanda, Wei Zhong Leong
In hematopoietic cell development, the transcriptional program is strictly regulated in a lineage- and stage-specific manner that requires a number of transcription factors to work in a cascade or in a loop, in addition to interactions with non-hematopoietic cells in the microenvironment. Disruption of the transcriptional program alters the cellular state and may predispose cells to the acquisition of genetic abnormalities. Early studies have shown that proteins that promote cell differentiation often serve as tumor suppressors, whereas inhibitors of those proteins act as oncogenes in the context of acute leukemia...
June 23, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28647392/a-novel-dual-inhibitor-of-microtubule-and-bruton-s-tyrosine-kinase-inhibits-survival-of-multiple-myeloma-and-osteoclastogenesis
#2
Manoj K Pandey, Krishne Gowda, Shen-Shu Sung, Thomas Abraham, Tulin Budak-Alpdogan, Giampolo Talamo, Sinisa Dovat, Shantu Amin
Bruton's tyrosine kinase (BTK) regulates many vital signaling pathways and play critical role in cell proliferation, survival, migration, and resistance. Earlier we reported that a small molecule KS99 is an inhibitor of tubulin polymerization. In the present study we explored that whether KS99 is a dual inhibitor of BTK and tubulin polymerization. While it is known that BTK is required for clonogenic growth, and resistance; and microtubules are essential for cancer cell growth; dual targeting of these two components has not been explored...
June 21, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28625745/lifelong-dietary-intervention-does-not-affect-hematopoietic-stem-cell-function
#3
Seka Lazare, Albertina Ausema, Aaffien C Reijne, Gertjan van Dijk, Ronald van Os, Gerald de Haan
Hematopoietic stem cells (HSC) undergo a profound functional decline during normal aging. As caloric or dietary restriction has been shown to delay multiple aspects of the aging process in many species, we here decided to explore the consequences of lifelong caloric restriction or, reversely, lifelong excess caloric intake for HSC numbers and function. Although caloric restriction prevented age-dependent increase in bone marrow cellularity, caloric restriction was not able to prevent functional decline of aged long-term hematopoietic stem cell functioning...
June 15, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28602946/whole-genome-analysis-reveals-unexpected-dynamics-of-mutant-subclone-development-in-a-patient-with-jak2-v617f-positive-chronic-myeloid-leukemia
#4
I Sloma, M Mitjavila-Garcia, O Feraud, F Griscelli, N Oudrhiri, S El Marsafy, E Gobbo, D Divers, A Proust, D M Smadja, C Desterke, A Carles, Y Ma, M Hirst, M A Marra, C J Eaves, A Bennaceur-Griscelli, A G Turhan
We report here the first use of whole genome sequencing (WGS) to examine the initial clonal dynamics in an unusual patient with chronic myeloid leukemia (CML) who presented in chronic phase (CP) with doubly marked BCR-ABL1(+)/JAK2(V617F)-mutant cells and over a 9 year period progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS showed the diagnostic cells also contained mutations in ASXL1, SEC23B, MAD1L1 and RREB1, as well as 12,000 additional uncommon DNA variants. WGS of endothelial cells generated from circulating precursors revealed many of these were shared with the CML clone...
June 7, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28596089/prkch-regulates-hematopoietic-stem-cell-function-and-predicts-poor-prognosis-in-acute-myeloid-leukemia
#5
Shaina N Porter, Jeffrey A Magee
Acute myeloid leukemia (AML) cells often co-opt normal hematopoietic stem cell (HSC) programs to drive neoplastic proliferation, and HSC-related gene expression signatures have been identified as biomarkers for poor prognosis in AML patients. We sought to identify new regulators of HSCs and AML cells from previously published HSC and leukemia stem cell (LSC) gene expression signatures. We identified PRKCH (Protein Kinase C eta) as a gene that is highly expressed in both mouse and human HSCs, as well as in LSCs from independent cohorts of AML patients...
June 5, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28552733/flt3-ligand-regulates-thymic-precursor-cells-and-hematopoietic-stem-cells-through-interactions-with-cxcr4-and-the-marrow-niche
#6
Kirsten M Williams, Amber R Moore, Philip J Lucas, Juin Wang, Catherine V Bare, Ronald E Gress
Impaired immune reconstitution after hematopoietic stem cell transplantation (HSCT) is attributed in part to impaired thymopoiesis. Recent data suggest that precursor input may be a point of regulation for the thymus. We hypothesized that administration of FLT3 ligand (FLT3L) would enhance thymopoiesis after adoptive transfer of aged, FLT3L-treated bone marrow (BM) to aged, Lupron-treated hosts by increasing murine HSC (Lin([minus])Sca1(+)c-Kit(+) [LSK] cells) trafficking and survival. In murine models of aged and young hosts, we show that FLT3L enhances thymopoiesis in aged, Lupron-treated hosts through increased survival and export of LSK cells via CXCR4 regulation...
May 26, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28527810/hif-1%C3%AE-stabilizing-agent-fg-4497-rescues-human-cd34-cell-mobilization-in%C3%A2-response-to-g-csf-in-immunodeficient-mice
#7
Bianca Nowlan, Kathryn Futrega, Marion E Brunck, Gail Walkinshaw, Lee E Flippin, Michael R Doran, Jean-Pierre Levesque
Granulocyte colony-stimulating factor (G-CSF) is used routinely in the clinical setting to mobilize hematopoietic stem progenitor cells (HSPCs) into the patient's blood for collection and subsequent transplantation. However, a significant proportion of patients who have previously received chemotherapy or radiotherapy and require autologous HSPC transplantation cannot mobilize the minimal threshold of mobilized HSPCs to achieve rapid and successful hematopoietic reconstitution. Although several alternatives to the G-CSF regime have been tested, few are used in the clinical setting...
May 17, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28506695/d816v-mutation-in-the-kit-gene-activation-loop-has-greater-cell-proliferative-and-anti-apoptotic-ability-than-n822k-mutation-in-core-binding-factor-acute-myeloid-leukemia
#8
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, the significance of which remains unclear. We previously reported that prognoses differ between the KIT D816V and N822K mutations. In the present study, we compared in vitro the cell-proliferative and anti-apoptotic ability of D816V and N822K. We transduced these KIT mutations into the interleukin-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-tumor-suppressor-and-drug-resistance-activities-of-samhd1
#9
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 involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits the permissiveness 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
#10
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-lscs-achilles-heel
#11
REVIEW
Yong-Mi Kim, Eun-Ji 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 reported. CSCs, in general, and LSCs, specifically with respect 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
#12
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 reported recently that the reprogramming factor Krüppel-like factor 4 (KLF4) has a 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
#13
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 understanding how these drugs interact is of the utmost importance. The pharmacokinetics of busulfan, melphalan, and cyclophosphamide, drugs commonly used for HSCT, are known to be affected by a variety of other 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/28456748/reprogramming-acute-myeloid-leukemia-into-sensitivity-for-retinoic-acid-driven-differentiation
#14
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 for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, an FLT3-ITD, an IDH1 mutation, and an overexpression of EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy...
April 27, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28408238/novel-roles-for-podocalyxin-in-regulating-stress-myelopoiesis-rap1a-and-neutrophil-migration
#15
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
#16
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/28457753/expression-of-cd25-on-leukemic-stem-cells-in-bcr-abl1-cml-potential-diagnostic-value-and-functional-implications
#17
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 chromosome and the related oncoprotein BCR-ABL1. The disease is characterized by an accumulation of myeloid precursor cells in the peripheral blood 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 (LSCs)...
July 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28456747/blos2-maintains-hematopoietic-stem-cells-in-the-fetal-liver-via-repressing-notch-signaling
#18
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 HSC/hematopoietic progenitor cell 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 the regulation of HSC proliferation and differentiation in the FL...
July 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28456746/genetically-engineered-mesenchymal-stromal-cells-produce-il-3-and-tpo-to-further-improve-human-scaffold-based-xenograft-models
#19
Marco Carretta, Bauke de Boer, Jenny Jaques, Antonella Antonelli, Sarah J Horton, Huipin Yuan, Joost D de Bruijn, Richard W J Groen, Edo Vellenga, Jan Jacob Schuringa
Recently, NOD-SCID IL2Rγ(-/-) (NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel 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. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO)...
July 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28450163/murine-hemogenic-endothelial-precursors-display-heterogeneous-hematopoietic-potential-ex%C3%A2-vivo
#20
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 [HE]), which is highly concentrated in the aorta-gonad-mesonephros region of the midgestation embryo. Here, we used clonal ex vivo assays, in which endothelial cells isolated from the midgestation aorta and vitelline and umbilical arteries are co-cultured on supportive stroma, to show that only about 0...
July 2017: Experimental Hematology
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