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Androgen Receptor Expression in Mantle Cell Lymphoma: Potential Novel Therapeutic ImplicationsOpen in a New Window

(Elahe A. Mostaghel, Paul S. Martin, Stephen Mongovin, Shani Frayo, Ailin Zhang, Kerstin L. Edlefsen, Oliver W. Press, Ajay K. Gopal) - 2017-01-20

 

Analysis of parameters that affect human hematopoietic cell outputs in mutant c-kit immunodeficient miceOpen in a New Window

Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect post-transplant reconstitution dynamics remain poorly understood. Here we show an equivalent level of human chimerism can be regenerated from human CD34+ cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2-6 month-old NOD-Rag1-/--IL2Rγc-/- (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient, NOD-Prkdcscid/scid-IL2Rγc-/- (NSG) hosts. (Paul H. Miller, Gabrielle Rabu, Margarita MacAldaz, David JHF. Knapp, Alice MS. Cheung, Kiran Dhillon, Naoto Nakamichi, Philip A. Beer, Leonard D. Shultz, R Keith Humphries, Connie J. Eaves) - 2017-01-10

 

Polycomb complexes PRC1 and their function in hematopoiesisOpen in a New Window

Hematopoiesis, the process by which blood cells are continuously produced, is one of the best studied differentiation pathways. Hematological diseases are associated to reiterated mutations in genes encoding important gene expression regulators, including chromatin regulators. Among them, the Polycomb group (PcG) of proteins is an essential system of gene silencing involved in the maintenance of cell identities during differentiation. PcG proteins assemble into two major types of Polycomb repressive complexes (PRC) endowed with distinct histone tail modifying activities. (Miguel Vidal, Katharzina Starowicz) - 2017-01-10

 

Induced Pluripotent Stem Cell Technology: A Window for Studying the Pathogenesis of Acquired Aplastic Anemia and Possible ApplicationsOpen in a New Window

Recent progress in human induced pluripotent stem cells (iPSCs) has opened the door to better understand the biology of human diseases, especially in rare disorders, such as acquired aplastic anemia (AA), in which the target hematopoietic tissues are depleted. The advent of somatic cell reprogramming has presented new routes for generating hematopoietic stem cells (HSCs) from patient-derived iPSCs and their differentiation into hematopoietic lineages. The purpose of this review is to discuss the recent advances in iPSC research technology and its potential applications in disease modeling for understanding the pathogenesis of bone marrow failure syndrome (BMFS) and the potential clinical utility of iPSC-derived cells. (Mahmoud Elbadry, J. Luis Espinoza, Shinji Nakao) - 2017-01-03

 

Governing Roles for Trib3 Pseudokinase During Stress ErythropoiesisOpen in a New Window

In response to anemia, the heightened production of erythropoietin (EPO) can sharply promote erythroid progenitor cell (EPC) formation. Specific mediators of such EPO- accelerated erythropoiesis, however, are not well understood. Presently, we first report that the expression of Trib3 in adult bone marrow EPCs in vivo is nominal at steady state, but strongly activated upon EPO challenge. In a knockout mouse model, Trib3 disruption modestly increased steady-state erythrocyte numbers, and decreased mean corpuscular volume. (Arvind Dev, Ruth Asch, Edward Jachimowicz, Nicole Rainville, Ashley Johnson, Emily Greenfest-Allen, Don M. Wojchowski) - 2017-01-03

 

Of hemangioblast, hemogenic endothelium and primitive versus definitive hematopoiesisOpen in a New Window

The types of progenitors generated during the successive stages of embryonic blood development are now fairly well characterized. The terminology used to describe these waves, however, can still be confusing. What is truly primitive? What is uniquely definitive? These questions become even more challenging to answer when blood progenitors are derived in vitro upon the differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). Similarly, the cellular origin of these blood progenitors can be controversial. (Georges Lacaud, Valerie Kouskoff) - 2016-12-31

 

Shipping mouse bone marrow: Keep it in the boneOpen in a New Window

(Ani E. Papazian, Youmna S. Kfoury, David T. Scadden) - 2016-12-31

 

Kinase signaling and targeted therapy for primary myelofibrosisOpen in a New Window

The myeloproliferative neoplasms (MPNs) are somatic mutation-driven hematologic malignancies characterized by bone marrow fibrosis and the accumulation of atypical megakaryocytes with reduced polyploidization in the primary myelofibrosis subtype of the MPNs. Increasing evidence points to a dominant role of abnormal megakaryocytes in disease initiation and progression. Here we review the literature related to kinase signaling pathways relevant to megakaryocyte differentiation and proliferation, including Aurora A kinase, RhoA/ROCK, and JAK/STAT, as well as the activities of their targeted inhibitors in models of the disease. (Qiong Yang, John D. Crispino, Qiang Jeremy Wen) - 2016-12-31

 

Letter to the Editor: Mutational analysis of hypermutation-related gene in acute leukemias and lymphomasOpen in a New Window

The POLE gene encodes the catalytic subunit of DNA polymerase ε (Polε), which is involved in DNA repair and chromosomal DNA replication [1]. The proofreading (exonuclease) function of Polε detects and removes misincorporated bases. Defects in this function due to POLE mutations may lead to a loss of replication fidelity and an increase in the mutational burden, resulting in tumor development. Germline mutations in POLE have been associated with colorectal cancer (CRC) predisposition [2]. Somatic mutations of POLE in the exonuclease domain are found in CRC and endometrial cancers that show association with hypermutability [3]. (Eun Ji Choi, Min Sung Kim, Nam Jin Yoo, Sug Hyung Lee) - 2016-12-26

 

Donor lymphocyte infusions in AML and MDS: Enhancing the graft-versus-leukemia effectOpen in a New Window

▪▪▪ (Guillermo Orti, Pere Barba, Laura Fox, Olga Salamero, Francesca Bosch, David Valcarcel) - 2016-12-24

 

Targeting the transcription factor Myb by small-molecule inhibitorsOpen in a New Window

The transcription factor Myb is a key regulator of hematopoietic cell proliferation, differentiation, and survival and has been implicated in the development of leukemia and several other human cancers. Pharmacological inhibition of Myb is therefore emerging as a potential therapeutic strategy. Recently, the first low-molecular-weight compounds that show Myb inhibitory activity have been identified. Characterization of these compounds suggests disruption of the protein–protein–interaction of Myb and the coactivator p300 as a suitable strategy to inhibit Myb. (Sagar Uttarkar, Jon Frampton, Karl-Heinz Klempnauer) - 2016-12-22

 

Preclinical approaches in chronic myeloid leukemia: From cells to systemsOpen in a New Window

Advances in the design of targeted therapies for the treatment of chronic myeloid leukemia (CML) have transformed the prognosis for patients diagnosed with this disease. However, leukemic stem cell persistence, drug intolerance, drug resistance, and advanced-phase disease represent unmet clinical needs demanding the attention of CML investigators worldwide. The availability of appropriate preclinical models is essential to efficiently translate findings from the bench to the clinic. Here we review the current approaches taken to preclinical work in the CML field, including examples of commonly used in vivo models and recent successes from systems biology-based methodologies. (Cassie J. Clarke, Tessa L. Holyoake) - 2016-12-22

 

Ixazomib suppresses human dendritic cell and modulates murine graft-versus-host disease in a schedule-dependent fashionOpen in a New Window

There is an abiding need for innovative approaches to the prevention of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Interest in prevention of GvHD by dendritic cell (DC) suppression has re-emerged since the introduction of proteasome inhibitors into clinical practice. Ixazomib is an orally bioavailable proteasome inhibitor with a rapid proteasome dissociation rate. We studied the effects of ixazomib on human DC maturation, viability, and cytokine production in vitro. (Ahmad Samer Al-Homsi, Austin Goodyke, Kelli Cole, Marlee Muilenburg, Michael McLane, Sarah Abdel-Mageed, Yuxin Feng) - 2016-12-19

 

EphA5 and EphA7 forward signaling enhances human hematopoietic stem and progenitor cell maintenance, migration, and adhesion via Rac1 activationOpen in a New Window

The proliferation, differentiation, adhesion, and migration of hematopoietic stem and progenitor cells (HSPCs) are dependent upon bone marrow stromal cells (BMSCs). In this study, we found that human primitive HSPCs (CD34+CD38−), but not lineage-committed hematopoietic cell populations, express the tyrosine kinase receptors EphA5 and EphA7. Moreover, we found that the ephrinA5 ligand, the high-affinity binding partner of EphA5 and EphA7, is highly expressed by primary human BMSCs. Previous studies have reported that interactions between EphA and ephrinA play important roles in hematopoietic cell trafficking; however, their role in BMSC support of hematopoiesis had not been described previously. (Thao M. Nguyen, Agnieszka Arthur, Andrew C.W. Zannettino, Stan Gronthos) - 2016-12-14

 

The BAF45a/PHF10 Subunit of SWI/SNF-like Chromatin Remodeling Complexes is Essential for Hematopoietic Stem Cell MaintenanceOpen in a New Window

The ability of hemopoietic stem cells to self-renew and differentiate into downstream lineages is dependent on specialized chromatin environments that establish and maintain stage-specific patterns of gene expression. However, the epigenetic factors responsible for mediating these regulatory events remain poorly defined. Here we provide evidence that BAF45a/PHF10, a subunit of SWI/SNF-like chromatin remodeling complexes, is essential for adult hemopoietic stem cell (HSC) maintenance and myeloid lineage development. (Veneta Krasteva, Gerald R. Crabtree, Julie A. Lessard) - 2016-12-05

 

From the bedside to the bench: new discoveries on blood cell fate and functionOpen in a New Window

Controversy and context: two words that exemplified this year's International Society for Experimental Hematology meeting. Leaders in the field of hematology from around the world gathered in San Diego in August of 2016 to discuss cutting-edge research on diverse topics such as hemoglobin switching, hematopoietic stem cell emergence, leukemogenesis, and aging. Major questions discussed included the “when, where, and how” of hematopoietic emergence, bone marrow residence, and disease origination. (Eirini Trompouki, Eugenia Flores-Figueroa, Daniel Lucas, Teresa V. Bowman) - 2016-12-05

 

Impairment of fetal hematopoietic stem cell function in the absence ofOpen in a New Window

Fanconi anemia (FA) results from mutations in the genes necessary for DNA damage repair and often leads to progressive bone marrow failure. Although the exhaustion of the bone marrow leads to cytopenias in FA patients as they age, evidence from human FA and mouse model fetal livers suggests that hematopoietic defects originate in utero, which may lead to deficient seeding of the bone marrow. To address this possibility, we examined the consequences of loss of Fancd2, a central component of the FA pathway. (Sakiko Suzuki, Ronny R. Racine, Nathan A. Manalo, Sharon B. Cantor, Glen D. Raffel) - 2016-11-30

 

Immunogenicity of murine mPEG-red blood cells and the risk of anti-PEG antibodies in human blood donorsOpen in a New Window

The immunocamouflage of non-ABO blood group antigens by membrane-grafted methoxypoly(ethylene glycol) (mPEG) may attenuate the risk of red blood cell (RBC) alloimmunization. However, concerns have been raised over the immunogenic risk of PEG and PEG-RBCs. To assess this risk, murine and human studies were performed. Mice were exposed to soluble PEG prior to, or between, multiple transfusions (∼60-day intervals) of control or mPEG-RBCs, and cell survival was determined by flow cytometry. In some studies, the control and mPEG-RBC groups were reversed after one or more transfusions. (Yevgeniya Le, Wendy M. Toyofuku, Mark D. Scott) - 2016-11-15

 

MLL-AF4 binds directly to a BCL-2 specific enhancer and modulates H3K27 acetylationOpen in a New Window

Survival rates for children and adults carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in acute lymphoblastic leukemia is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in-frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we found that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. In the study described here, we performed a detailed analysis of MLL-AF4 regulation of the entire BCL-2 family. (Laura Godfrey, Jon Kerry, Ross Thorne, Emmanouela Repapi, James O.J. Davies, Marta Tapia, Erica Ballabio, Jim R. Hughes, Huimin Geng, Marina Konopleva, Thomas A. Milne) - 2016-11-14

 

expression in the bone marrow niche is not essential for hematopoietic maintenanceOpen in a New Window

Myb-Like SWIRM and MPN domains 1 (MYSM1) is a chromatin-binding protein, essential for hematopoietic stem cell (HSC) maintenance and differentiation in humans and mouse models. HSCs in mammalian bone marrow exist in close interactions with many non-hematopoietic cell types in their microenvironment, collectively known as the bone marrow niche. Although cell-intrinsic activities of MYSM1 within the hematopoietic cells are known to play an important role in hematopoietic homeostasis, Mysm1 expression is also widely observed in non-hematopoietic cells, and MYSM1 is implicated as an important regulator of mesenchymal stem cell differentiation, osteoblast function, and adipogenesis within the bone marrow. (Jessica C. Petrov, Anastasia Nijnik) - 2016-11-08

 

Variable aldehyde dehydrogenase activity and effects on chemosensitivity of primitive human leukemic cellsOpen in a New Window

Aldehyde dehydrogenase (ALDH) activity is an established feature of primitive normal human hematopoietic cells, in which it has been associated with a high expression of the 1A1 isoform of ALDH. High ALDH 1A1 activity has been reported to also characterize cells that propagate malignant populations arising in other tissues, but the regulation and basis of ALDH activity in primary human leukemic cells has not been well studied. We obtained samples from patients with newly diagnosed acute myeloid leukemia (AML; n = 21) and chronic myeloid leukemia (CML; n = 8) and analyzed different phenotypically and functionally defined subsets for their ALDH activity using the ALDEFLUOR® kit and expression of the ALDH1A1 gene. (Anja Bogen, Christian Buske, Wolfgang Hiddemann, Stefan K. Bohlander, Oliver Christ) - 2016-11-05

 

‘Off-the-shelf’ immunotherapy with iPSC-derived rejuvenated cytotoxic T lymphocytesOpen in a New Window

Adoptive T-cell therapy to target and kill tumor cells shows promise and induces durable remissions in selected malignancies. However, for most cancers, clinical utility is limited. Cytotoxic T lymphocytes continuously exposed to viral or tumor antigens, with long-term expansion, may become unable to proliferate (“exhausted”). To exploit fully rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T lymphocytes is a potentially powerful approach. We review recent progress in engineering iPSC-derived T cells and prospects for clinical translation. (Miki Ando, Hiromitsu Nakauchi) - 2016-11-05

 

MOZ and BMI1 act synergistically to maintain hematopoietic stem cellsOpen in a New Window

Chromatin plays a central role in maintaining hematopoietic stem cells and during their stepwise differentiation. Although a large number of histone modifications and chromatin-modifying enzymes have been identified, how these act in concert to produce specific phenotypic outcomes remains to be established. MOZ (KAT6A) is a lysine acetyltransferase and enhances transcription at target gene loci. In contrast, the Polycomb group protein BMI1 (PCGF4) is part of the transcriptionally repressive PRC1 complex. (Bilal N. Sheikh, Donald Metcalf, Anne K. Voss, Tim Thomas) - 2016-10-20

 

Everolimus restrains the IL-17A-dependent osteoclast-like transdifferentiation of dendritic cells in multiple myelomaOpen in a New Window

Interleukin-17A (IL-17A) promotes the osteoclast (OC)-like differentiation of dendritic cells (DCs) in multiple myeloma (MM) and contributes to the pathogenesis of myeloma bone disease (MBD). In our study, everolimus (EVR) abrogated the in vitro OC-like activity of DCs from 12 MM patients significantly. Exploring the EVR effects, we found that the inhibition of the osteoerosive activity of OC-DCs was mostly due to the blockade of signals driven by the IL-17A receptor toward the CCAAT/enhancer-binding protein beta/musculoaponeurotic fibrosarcoma oncogene homolog B axis Therefore, MM patients with MBD would probably benefit from mammalian target of rapamycin inhibition. (Marco Tucci, Stefania Stucci, Anna Passarelli, Stella D'Oronzo, Franco Silvestris) - 2016-10-17

 

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
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2/21/2017
ISEH Webinar: Epigenetic regulation of normal and malignant hematopoiesis

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