Volume 4.24 | Jun 25

Hematopoiesis News 4.24 June 25, 2013
Hematopoiesis News
     In this issue: Publications | Reviews | Science News | Industry News | Policy News | Events | Jobs
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TOP STORY
Drug Shows Potential as Safe and Effective for Chronic Leukemia, Mantle Cell Lymphoma
Two clinical studies suggest that the novel agent ibrutinib shows real potential as a safe, effective, targeted treatment for adults with chronic lymphocytic leukemia and for patients with mantle cell lymphoma. [Press release from The Ohio State University discussing two online prepublications in The New England Journal of Medicine] Press Release | Full Article 1 | Full Article 2 | Video

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PUBLICATIONS (Ranked by impact factor of the journal)

LABORATORY RESEARCH

The Ubiquitin Ligase FBXW7 Modulates Leukemia-Initiating Cell Activity by Regulating MYC Stability
Missense FBXW7 mutations are prevalent in various tumors, including T cell acute lymphoblastic leukemia. To study the effects of such lesions, the authors generated animals carrying regulatable Fbxw7 mutant alleles. They showed that these mutations specifically bolster cancer-initiating cell activity in collaboration with Notch1 oncogenes but spare normal hematopoietic stem cell function. [Cell]
Abstract | Graphical Abstract | Press Release

In Vivo Mapping of Notch Pathway Activity in Normal and Stress Hematopoiesis
Researchers generated and describe animal models to identify and fate-map stem and progenitor cells expressing each Notch receptor, delineated Notch pathway activation, and performed in vivo gain- and loss-of-function studies dissecting Notch signaling in early hematopoiesis. These models provide comprehensive genetic maps of lineage-specific Notch receptor expression and activation in hematopoietic stem and progenitor cells. [Cell Stem Cell] Abstract | Graphical Abstract

miR-9 Is an Essential Oncogenic MicroRNA Specifically Overexpressed in Mixed Lineage Leukemia-Rearranged Leukemia
Acute myeloid leukemia (AML) with chromosomal translocations involving the mixed lineage leukemia (MLL) gene are usually associated with poor survival. Through a large-scale, genomewide microRNA expression assay, researchers showed that microRNA-9 (miR-9) is the most specifically up-regulated miRNA in MLL-rearranged AML compared with both normal control and non-MLL-rearranged AML. They demonstrated that miR-9 is a direct target of MLL fusion proteins and can be significantly up-regulated in expression by the latter in human and mouse hematopoietic stem/progenitor cells. [Proc Natl Acad Sci USA] Abstract

IRP1 Regulates Erythropoiesis and Systemic Iron Homeostasis by Controlling HIF2a mRNA Translation
Investigators showed that the disruption of mouse IRP1, but not IRP2, leads to profound HIF2a-dependent abnormalities in erythropoiesis and systemic iron metabolism. Thus, 4-6 week old IRP1-/- mice exhibit splenomegaly and extramedullary hematopoiesis, which is corrected in older animals. These erythropoietic abnormalities are caused by translational de-repression of HIF2a mRNA and subsequent accumulation of HIF2a, which induces expression of erythropoietin. [Blood] Abstract

Notch1 Regulates AKT Activation Loop (T308) Dephosphorylation through Modulation of the PP2A Phosphatase in PTEN-Null T-Cell Acute Lymphoblastic Leukemia Cells
Mutational loss of phosphatase and tensin homolog (PTEN) is frequent in T-cell acute lymphoblastic leukemia (T-ALL) and promotes resistance to ?-secretase inhibitors (GSIs) due to AKT activation. GSI treatments increased AKT-T308 phosphorylation and signaling in PTEN-deficient, GSI-resistant T-ALL cell lines, suggesting that Notch1-represses AKT independent of its PTEN transcriptional effects. [J Biol Chem] Abstract | Full Article

Combining CAR T Cells and the Bcl-2 Family Apoptosis Inhibitor ABT-737 for Treating B-Cell Malignancy
Chimeric antigen receptor (CAR) T cells targeting CD19 were generated from healthy donors as well as from precursor-B acute lymphoblastic leukemia patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. [Cancer Gene Ther] Abstract

Free Iron Catalyzes Oxidative Damage to Hematopoietic Cells/ Mesenchymal Stem Cells In Vitro and Suppresses Hematopoiesis in Iron Overload Patients
Transfusional iron overload is of major concern in hematologic disease. Iron overload related dyserythropoiesis and reactive oxygen species (ROS) related damage to hematopoietic stem cell function are major setbacks in treatment of such disorders. Scientists therefore aimed to investigate the effect of iron overload on hematopoiesis of patients and explore the role of ROS in iron induced oxidative damage in hematopoietic cells and microenvironment in vitro. [Eur J Haematol] Abstract

CLINICAL RESEARCH

Impaired B-Cell Reconstitution in Children after Chemotherapy for Standard or Medium Risk Acute Precursor B-Lymphoblastic Leukemia
Immune reconstitution was studied in a homogenous cohort of 48 children with standard- or medium-risk acute lymphoblastic leukemia (ALL) treated according to the ALL-BFM-protocol. Whereas the T-cell compartment is only moderately affected and recovered to normal levels quickly after treatment cessation, B-cells are significantly reduced during and after therapy. Especially the naïve B-cell compartment declines. [Leuk Lymphoma] Abstract

Usefulness of Allogeneic Hematopoietic Stem Cell Transplantation in First Complete Remission for Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm with Skin Involvement: A Case Report and Review of Literature
The authors treated with acute lymphoblastic leukemia-type regimen for a child with blastic plasmacytoid dendritic cell neoplasma (BPDCN) with skin and leukemic involvement. She has been disease-free for 4 years after allogeneic bone marrow transplantation in first complete remission. In 33 cases of pediatric BPDCN, the over survival was significantly lower in the patients with skin manifestation than those without cutaneous involvement. [Pediatr Blood Cancer] Abstract

How Ex Vivo Models Drive Progress in HIV Research: Read the Research Profiles

REVIEWS

Multifaceted Roles of GSK-3 and Wnt/ß-Catenin in Hematopoiesis and Leukemogeneis: Opportunities for Therapeutic Intervention
The authors discuss the roles that glycogen synthase kinase-3 (GSK-3) plays in hematopoiesis and leukemogenesis and how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/ß-catenin, PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Notch and others. They also discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. [Leukemia] Abstract | Full Article

Heparin-Binding Epidermal Growth Factor-Like Growth Factor/Diphtheria Toxin Receptor in Normal and Neoplastic Hematopoiesis
The authors outline the main activities of heparin-binding EGF-like growth factor in connection with normal or neoplastic differentiative or proliferative events taking place primitively in the hematopoietic microenvironment. [Toxins] Abstract | Full Article

The Role of Vitamin D in Hematologic Disease and Stem Cell Transplantation
The authors summarize the role of vitamin D in normal hematopoiesis, discuss ways in which vitamin D may improve outcomes, and discuss a potential role of vitamin D for treating hematologic disorders and modulating the immune system to improve the outcome of allogeneic stem cell transplant. [Nutrients] Abstract | Full Article

Visit our reviews page to see a complete list of reviews in the hematopoiesis research field.

SCIENCE NEWS

CTI Announces New Data Demonstrating the Safety and Tolerability Profile of Pacritinib in Patients with Myelofibrosis
Cell Therapeutics, Inc. (CTI) announced results from a pooled analysis of data from completed Phase I and II studies of pacritinib, an oral JAK2/FLT3 inhibitor, demonstrating the safety and tolerability profile of pacritinib in patients with myelofibrosis. An integrated safety analysis of four completed Phase I and II studies totaled 191 patients who were treated with pacritinib for myeloid, primarily myelofibrosis, or lymphoid malignancies to quantify clinical toxicities, with a focus on hematologic effects. [Press release from Cell Therapeutics, Inc. discussing research presented at the 18th Congress of the European Hematology Association, Stockholm] Press Release


Alnylam Scientists Present Pre-Clinical Data with ALN-CC5, an RNAi Therapeutic Targeting Complement Component C5 for the Treatment of Complement-Mediated Diseases
Alnylam scientists presented pre-clinical results showing potent, dose-dependent, and durable RNAi-mediated knockdown of serum C5 and inhibition of complement-mediated hemolytic activity of approximately 90% with a subcutaneously administered RNAi therapeutic. [Press release from Alnylam Pharmaceuticals, Inc. discussing research presented at the 6th International Conference on Complement Therapeutics, Kos] Press Release


Affimed Reports Phase I Clinical Data for Its Immunotherapy AFM13 in Relapsing/Refractory Hodgkin Lymphoma Patients
Affimed Therapeutics AG announced encouraging results from a phase I clinical trial of AFM13 as monotherapy for the treatment of patients with advanced relapsing/refractory Hodgkin lymphoma. AFM13 appears to be well tolerated with evidence of meaningful anti-tumor activity, including partial responses and stable diseases. AFM13 is a bispecific TandAb antibody recruiting host NK cells via its CD16A-binding domains to engage and kill CD30-positive malignant cells. [Press release from Affimed Therapeutics AG discussing research presented at the 12th International Conference on Malignant Lymphoma, Lugano]
Press Release

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INDUSTRY NEWS

FDA Puts Cell Therapeutics Blood Cancer Drug on Hold after Death from Myocarditis
Cell Therapeutics Inc said the U.S. Food and Drug Administration (FDA) has placed a partial clinical hold on the company’s experimental blood cancer drug after the death of a patient. The patient, being treated with the drug tosedostat in combination with a chemotherapy drug, died of myocarditis, or infection of the heart muscle, the company said in a regulatory filing. [Thompson Reuters] Press Release


MEI Pharma Initiates Phase II Clinical Trial of Pracinostat and Vidaza® in Frontline Myelodysplastic Syndrome
MEI Pharma, Inc. announced that the first patients have been dosed in a Phase II clinical trial of its lead drug candidate Pracinostat in combination with Vidaza (azacitidine) in patients with previously untreated intermediate-2 or high-risk myelodysplastic syndrome (MDS). The randomized, double-blind trial is designed to evaluate the safety and efficacy of Pracinostat compared to placebo when combined with Vidaza, a drug approved by the U.S. Food & Drug Administration for the treatment of MDS. [MEI Pharma, Inc.]
Press Release


Celebrating 25 Years and Counting: Leukemia and Lymphoma Society’s “Team In Training” Goes the Distance and Beyond for Blood Cancer Patients

This year alone, The Leukemia & Lymphoma Society (LLS) is supporting more than 300 research projects with one goal in mind: Discovering lifesaving therapies for blood cancer patients. And in 2013, “Team In Training” (TNT), a flagship LLS fundraising campaign and the world’s first and largest endurance sports training program, is marking its landmark 25th anniversary. To date, TNT has helped LLS invest more than $875 million in research to discover and deliver breakthrough cancer treatments that are saving lives today. [PR Newswire Association, LLC] Press Release

POLICY NEWS

National Institutes of Health (United States)

Food and Drug Administration (United States)
 
Center for Biologics Evaluation and Research (United States)
 
European Medicines Agency (European Union)

Medicines and Healthcare Products Regulatory Agency (United Kingdom)

Therapeutic Goods Administration (Australia)

EVENTS

NEW 46th Annual Meeting of the Society for Leukocyte Biology
October 20-22, 2013
Newport, United States


Visit our events page to see a complete list of events in the hematopoiesis community.

JOB OPPORTUNITIES
NEW Research Associate (Assistant Professor) – Pediatric Hematology/Oncology (The University of Chicago)

Postdoctoral Research Fellow – Hematology/Pharmacology (Thomas Jefferson University, Cardeza Foundation for Hematologic Research)

Postdoctoral Positions – Stem Cell Biology and Epigenetics (University of Wisconsin-Madison)

Director of Cell Processing Facility (S L Collins Associates, Inc.)

PhD Student Position – Hematopoietic Stem Cells (Katholieke Universiteit Leuven)

Research Associate – Stem Cell and Leukemia Epigenetics (King’s College London)

Postdoctoral Fellow – Radiobiology and Hematopoietic Stem Cell Biology (Indiana University School of Medicine)

Postdoctoral Researcher – Hematopoietic Stem Cells (Albert Einstein College of Medicine)

Postdoctoral Fellow – Stem Cells and Cancer (Tsinghua University)

Postdoctoral Fellow – Stem Cell and Cancer Biology (Johns Hopkins University School of Medicine)

Studentship – Novel Mechanisms in Blood Cancers Drug-Resistance (University of East Anglia)


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