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


Murine hemogenic endothelial precursors display heterogeneous hematopoietic potentialOpen 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), 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 0.1%, 1.3% and 0.29% of E9.5, E10.5 and E11.5 endothelium are functional hemogenic endothelium, 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 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. (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 should 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 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. (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 with reported roles in renal podocyte diaphragm slit development, vascular cell integrity, and the progression of blood, breast, and prostate cancers. Roles for Podxl during non-malignant hematopoiesis, however, are largely undefined. Presently we have developed a Vav-Cre Podxl knockout 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 GCSF (granulocyte colony stimulating factor) in myeloid progenitors, and by TPO (thrombopoietin) in HSCs. (Pan Li, Aldona A. Karaczyn, Rose McGlauflin, Amanda Favreau, Edward Jachimowicz, Calvin Vary, Kailin Xu, Don M. Wojchowski, Pradeep Sathyanarayana) - 2017-04-10


Targeted Deletion of the Hoxa Cluster Affects B Lymphopoiesis Through Depletion of 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 (LSC) in the development of minimal residual disease (MRD), it is critical to use therapeutic interventions that target LSC population to prevent disease relapse. 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 (Emanuele G. Coci, Nadine Thau-Habermann, Tobias Maetzig, Zhixiong Li, Christoph Klein, Susanne Petri, Axel Schambach) - 2014-10-28
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8/24/2017 » 8/27/2017
ISEH 46th Annual Meeting - Frankfurt, Germany

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