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HIF-1α stabilizing agent FG-4997 rescues human CD34 cell mobilization in response to G-CSF in immuno-deficient miceOpen in a New Window

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. (Bianca Nowlan, Katarzyna Futrega, Marion E. Brunck, Gail Walkinshaw, Lee E. Flippin, Michael R. Doran, Jean-Pierre Levesque) - 2017-05-17

 

D816V mutation in the gene activation loop has a greater cell proliferative and anti-apoptotic ability than N822K mutation in core binding factor-acute myeloid leukemiaOpen in a New Window

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 KITD816V, TF-1 KITN822K). (Ikuko Omori, Hiroki Yamaguchi, Koichi Miyake, Noriko Miyake, Tomoaki Kitano, Koiti Inokuchi) - 2017-05-12

 

With me or against me: Tumour Suppressor and Drug Resistance Activities of SAMHD1Open in a New Window

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. (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) - 2017-05-11

 

Reciprocal regulation between hepcidin and erythropoiesis and its therapeutic application in erythroid disordersOpen in a New Window

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. (Caiyi Wang, Zheng Fang, Zesen Zhu, Jing Liu, Huiyong Chen) - 2017-05-10

 

Development of an assay for cellular efflux of pharmaceutically active agents and its relevance to understanding drug interactionsOpen in a New Window

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. (Benigno C. Valdez, Moustapha Hassan, Borje S. Andersson) - 2017-05-04

 

CBP/Catenin Antagonists: Targeting LSC’s Achilles HeelOpen in a New Window

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. (Yong-mi Kim, EunJi Gang, Michael Kahn) - 2017-05-04

 

Novel tumor suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemiaOpen in a New Window

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. (Ye Shen, Taylor J. Chen, H. Daniel Lacorazza) - 2017-05-04

 

Expression of CD25 on leukemic stem cells in BCR-ABL1 CML: Potential diagnostic value and functional implicationsOpen in a New Window

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). (Irina Sadovnik, Harald Herrmann, Gregor Eisenwort, Katharina Blatt, Gregor Hoermann, Niklas Mueller, Wolfgang R. Sperr, Peter Valent) - 2017-04-27

 

Genetically engineered mesenchymal stromal cells producing IL3 and TPO to further improve human scaffold-based xenograft modelsOpen in a New Window

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. (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) - 2017-04-26

 

Reprogramming acute myeloid leukemia into sensitivity for retinoic acid-driven differentiationOpen in a New Window

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. (Noortje van Gils, Han J.M.P. Verhagen, Linda Smit) - 2017-04-26

 

BLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signalingOpen in a New Window

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. (Qiuping He, Suwei Gao, Junhua Lv, Wei Li, Feng Liu) - 2017-04-26

 

Murine hemogenic endothelial precursors display heterogeneous hematopoietic potential ex vivoOpen in a New Window

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 0.1%, 1.3%, and 0.29% of E9.5, E10.5, and E11.5 endothelium are functional HE, respectively. (Miguel Ganuza, Brandon Hadland, Ashley Chabot, Chen Li, Guolian Kang, Irwin Bernstein, Shannon McKinney-Freeman) - 2017-04-24

 

Lkb1 deletion in murine B lymphocytes promotes cell death and cancerOpen in a New Window

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. (George P. Souroullas, Yuri Fedoriw, Louis M. Staudt, Norman E. Sharpless) - 2017-04-20

 

Stability of patient-specific features of altered DNA replication timing in xenografts of primary human acute lymphoblastic leukemiaOpen in a New Window

Genome-wide DNA replication timing (RT) profiles reflect the global three-dimensional 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. (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) - 2017-04-19

 

Adult T-type lymphoblastic lymphoma: Treatment advances and prognostic indicatorsOpen in a New Window

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 may help further extend T-LBL patient survival. (Stéphane Lepretre, Carlos Graux, Aurore Touzart, Elizabeth Macintyre, Nicolas Boissel) - 2017-04-13

 

Epo reprograms the epigenome of erythroid cellsOpen in a New Window

The hormone erythropoietin (Epo) is required for erythropoiesis, yet its molecular mechanism of action remains poorly understood, particularly with respect 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. (Andrea A. Perreault, Mary Lauren Benton, Mark J. Koury, Stephen J. Brandt, Bryan J. Venters) - 2017-04-11

 

Novel roles for podocalyxin in regulating stress myelopoiesis, Rap1a, and neutrophil migrationOpen in a New Window

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. (Pan Li, Aldona A. Karaczyn, Rose McGlauflin, Amanda J. Favreau-Lessard, Edward Jachimowicz, Calvin P. Vary, Kailin Xu, Don M. Wojchowski, Pradeep Sathyanarayana) - 2017-04-10

 

Targeted deletion of the cluster affects B lymphopoiesis through depletion of early lymphoid progenitorsOpen in a New Window

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. (Charles-Étienne Lebert-Ghali, Alexander Thompson, Heather J. Melichar, Janet J. Bijl) - 2017-04-05

 

Role of mTORC1–S6K1 signaling pathway in regulation of hematopoietic stem cell and acute myeloid leukemiaOpen in a New Window

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. (Joydeep Ghosh, Reuben Kapur) - 2017-03-22

 

Perspective: A defined role for multiple Fanconi anemia gene products in DNA-damage-associated ubiquitinationOpen in a New Window

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. (Winnie Tan, Andrew J. Deans) - 2017-03-15

 

Pharmacological inhibition of LSD1 and mTOR reduces mitochondrial retention and associated ROS levels in the red blood cells of sickle cell diseaseOpen in a New Window

Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs), which accelerates their hemolysis. (Ramasamy Jagadeeswaran, Benjamin A. Vazquez, Muthusamy Thiruppathi, Balaji B. Ganesh, Vinzon Ibanez, Shuaiying Cui, James D. Engel, Alan M. Diamond, Robert E. Molokie, Joseph DeSimone, Donald Lavelle, Angela Rivers) - 2017-02-23

 

Rat acute GvHD is Th1 driven and characterized by predominant donor CD4 T-cell infiltration of skin and gutOpen in a New Window

Acute graft-versus-host disease (aGvHD) remains a significant hurdle to successful treatment of many hematological disorders. The disease is caused by infiltration of alloactivated donor T cells primarily into the gastrointestinal tract and skin. Although cytotoxic T cells mediate direct cellular damage, T helper (Th) cells differentially secrete immunoregulatory cytokines. aGvHD is thought to be initiated primarily by Th1 cells but a consensus is still lacking regarding the role of Th2 and Th17 cells. (Margherita Boieri, Pranali Shah, Dasaradha Jalapothu, Olena Zaitseva, Lutz Walter, Bent Rolstad, Christian Naper, Ralf Dressel, Marit Inngjerdingen) - 2017-02-23

 

The Calreticulin control of human stress erythropoiesis is impaired by V617F in polycythemia veraOpen in a New Window

Calreticulin (CALR) is a Ca2+-binding protein that shuttles among cellular compartments with proteins bound to its N/P domains. The knowledge that activation of the human erythropoietin receptor induces Ca2+ fluxes prompted us to investigate the role of CALR in human erythropoiesis. As shown by Western blot analysis, erythroblasts generated in vitro from normal sources and JAK2V617F polycythemia vera (PV) patients expressed robust levels of CALR. However, Ca2+ regulated CALR conformation only in normal cells. (Mario Falchi, Lilian Varricchio, Fabrizio Martelli, Manuela Marra, Orietta Picconi, Agostino Tafuri, Gabriella Girelli, Vladimir N. Uversky, Anna Rita Migliaccio) - 2017-02-20

 

The evolving view of the hematopoietic stem cell nicheOpen in a New Window

Hematopoietic stem cells (HSCs) reside in specialized microenvironments known as niches. The niche is essential to support HSC function and to maintain a correct balance between self-renewal and differentiation. Recent advances in defining different mesenchymal and endothelial bone marrow cell populations, as well as hematopoietic stem and progenitor cells, greatly enhanced our understanding of these niches and of the molecular mechanisms by which they regulate HSC function. In addition to the role in maintaining HSC homeostasis, the niche has also been implicated in the pathogenesis of blood disorders including hematological malignancies. (Isabel Beerman, Tiago C. Luis, Sofie Singbrant, Cristina Lo Celso, Simon Méndez-Ferrer) - 2017-02-10

 

Application of vitamin D and vitamin D analogs in acute myelogenous leukemiaOpen in a New Window

Acute myeloid leukemia (AML) is characterized by the accumulation of malignant, transformed immature hematopoietic myeloid precursors that have lost their ability to differentiate and proliferate normally. Current treatment for AML requires intensive cytotoxic chemotherapy and results in significant morbidity and mortality, especially in older patients. Effective and better-tolerated treatment is urgently needed. Studies have shown that 1α,25-dihydroxyvitamin D3 (1,25-D3, active VD3) or vitamin D analogs (VDAs) can potently differentiate AML cells in vitro and ex vivo, which led to early clinical trials in AML and myelodysplastic syndrome patients. (Huynh Cao, Yi Xu, Rosalia de Necochea-Campion, David J. Baylink, Kimberly J. Payne, Xiaolei Tang, Christina Ratanatharathorn, Yong Ji, Saied Mirshahidi, Chien-Shing Chen) - 2017-02-04

 

TEMPORARY REMOVAL: Assessment of hematopoietic and neurologic pathophysiology of -associated protein X-1 deficiency in a -knockout mouse modelOpen in a New Window

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated.The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. (Emanuele G. Coci, Nadine Thau-Habermann, Tobias Maetzig, Zhixiong Li, Christoph Klein, Susanne Petri, Axel Schambach) - 2014-10-28
more Calendar

5/30/2017
ISEH Webinar: How to get your blood(y) CRISPR/Cas9 to work

8/24/2017 » 8/27/2017
ISEH 46th Annual Meeting - Frankfurt, Germany

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