Hematopoiesis News 8.08 February 28, 2017 | |
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TOP STORYTargeting a CAR to the TRAC Locus with CRISPR/Cas9 Enhances Tumor Rejection Investigators showed that directing a CD19-specific chimeric antigen receptor (CAR) to the T-cell receptor α constant (TRAC) locus not only results in uniform CAR expression in human peripheral blood T cells, but also enhances T-cell potency, with edited cells vastly outperforming conventionally generated CAR T cells in a mouse model of acute lymphoblastic leukemia. [Nature] Abstract | Press Release | |
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PUBLICATIONS(Ranked by impact factor of the journal)Clonal Hematopoiesis Associated with TET2 Deficiency Accelerates Atherosclerosis Development in Mice The authors studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient mice. They found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. [Science] Abstract Researchers showed that an RNA-binding protein, QKI5, activates the processing of primary miR-124-1 (pri-124-1) during erythropoiesis. QKI5 recognizes a distal QKI response element and recruits Microprocessor through interaction with DGCR8. Furthermore, the recruited Microprocessor is brought to pri-124-1 stem loops by a spatial RNA-RNA interaction between two complementary sequences. [Cell Research] Abstract Downregulation of GATA1 Drives Impaired Hematopoiesis in Primary Myelofibrosis Scientists have revealed that megakaryocytes in primary myelofibrosis showed impaired maturation that is associated with reduced GATA1 protein. In investigating the cause of GATA1 downregulation, their gene-expression study revealed the presence of the RPS14-deficient gene signature, which is associated with defective ribosomal protein function and linked to the erythroid lineage in 5q deletion myelodysplastic syndrome. [J Clin Invest] Full Article Cobll1 Is Linked to Drug Resistance and Blastic Transformation in Chronic Myeloid Leukemia Researchers report Cordon-bleu protein-like 1 (Cobll1) as a distinct molecular marker associated with drug resistance as well as progression to blast crisis. In detail, Cobll1 increases IKKγ stability, leading to NF-κB activation and reduction of nilotinib-dependent apoptosis, suggesting Cobll1-mediated NF-κB could be involved in drug resistance. [Leukemia] Abstract The T-ALL Related Gene BCL11B Regulates the Initial Stages of Human T Cell Differentiation Through loss of function studies researchers showed BCL11B, a transcription factor recurrently mutated T-cell acute lymphoblastic leukemia (T-ALL), is essential for T-lineage commitment, particularly the repression of NK and myeloid potentials and the induction of T-lineage genes, during the initial stages of human T-cell differentiation. In gain of function studies, BCL11B inhibited growth of and induced a T-lineage transcriptional program in T-ALL cells. [Leukemia] Abstract PUMILIO/FOXP1 Signaling Drives Expansion of Hematopoietic Stem/Progenitor and Leukemia Cells Researchers demonstrated that FOXP1 by itself supports hematopoietic stem/progenitor cell and leukemic cell growth, thus mimicking PUM activities. Mechanistically, FOXP1 represses the expression of the p21-CIP1 and p27-KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and pro-apoptotic activities. [Blood] Abstract Clonal Reversal of Aging-Associated Stem Cell Lineage Bias via a Pluripotent Intermediate Scientists combined genetic barcoding of aged murine hematopoietic stem cells (HSCs) with the generation of induced pluripotent stem (iPS) cells. This allowed them to specifically focus on aged HSCs presenting with a pronounced lineage skewing, a hallmark of HSC aging. Functional and molecular evaluations revealed hematopoiesis from these iPS clones to be indistinguishable from that associating with young mice. [Nat Commun] Full Article Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia Investigators analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. [Cell Rep] Full Article | Graphical Abstract Due to difficulties in establishing stable maintenance and expansion of hematopoietic stem cells (HSCs) in vitro, their insufficient supply is a major constraint to transplantation studies. To solve these problems researchers developed a fully defined, all-recombinant protein-based culture system. Through this system, they identified hemopexin and interleukin-1α as responsible for HSC maintenance in vitro. [Stem Cell Reports] Full Article | Graphical Abstract Frequency and clinical relevance of mutations in ID3, TCF3 and CCND3 were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-cell Non-Hodgkin lymphoma patients of the Berlin-Frankfurt-Munster group (NHL-BFM). Mutation frequency was 78% (ID3), 13% (TCF3) and 36% (CCND3) in Burkitt lymphoma. ID3 and CCND3 mutations were associated with more advanced stages of the disease in MYC rearrangement positive Burkitt lymphoma. [Haematologica] Abstract Investigators showed that SP1 is the major driver of protein kinase CβII (PKCβII)expression in chronic lymphocytic leukemia (CLL) cells where enhanced association of this transcription factor with the PRKCB promoter is likely because of the presence of histone marks permissive of gene activation. [Sci Rep] Full Article Mutational Landscape Reflects the Biological Continuum of Plasma Cell Dyscrasias Scientists subjected 90 patients covering a biological spectrum of plasma cell dyscrasias to next-generation sequencing gene panel analysis on unsorted bone marrow. A total of 64 different mutations in 8 genes were identified in this cohort. NRAS, KRAS, TP53, BRAF and CCND1 were the most commonly mutated genes in all patients. [Blood Cancer J] Full Article CLINICAL RESEARCHScientists report on the measurement of minimal residual disease (MRD), by multicolour flow-cytometry in one centralized laboratory, in 142 children with newly diagnosed acute myeloid leukemia (AML) enrolled in the Associazione Italiana di EmatoOncologia Pediatrica-AML 2002/01 trial. [Br J Haematol] Abstract | |
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REVIEWSThe authors summarize existing data on allogeneic hematopoietic cell transplantation in patients with refractory or relapsed acute myeloid leukemia and explore novel approaches with the potential to improve outcomes in this patient population. [Bone Marrow Transplant] Abstract Visit our reviews page to see a complete list of reviews in the hematopoiesis research field. | |
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INDUSTRY NEWSGamida Cell announced that the first patient has been transplanted in the company’s Phase III study of NiCord®, in development as a cure for patients with blood cancer who do not have a fully matched donor required for bone marrow transplantation, a potentially $3 billion market. NiCord has an FDA Breakthrough Therapy Designation as well as FDA and EMA orphan drug designations. [Gamida Cell] Press Release Amgen announced positive results from a planned overall survival (OS) interim analysis of the Phase III head-to-head ENDEAVOR trial. The study met the key secondary endpoint of OS, demonstrating that patients with relapsed or refractory multiple myeloma treated with KYPROLIS® and dexamethasone lived 7.6 months longer than those treated with Velcade® and dexamethasone. [Amgen] Press Release Merck & Co., Inc. announced results of the pivotal Phase III clinical study of letermovir, an investigational antiviral medicine for the prevention of clinically-significant CMV infection in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT), also known as bone marrow transplant. The study met its primary efficacy endpoint, showing that significantly fewer patients with undetectable CMV DNA at the start of study treatment developed clinically significant CMV infection through Week 24 post-HSCT. [Merck & Co., Inc.] Press Release Celgene International Sà rl announced that the European Commission has approved REVLIMID® as monotherapy for the maintenance treatment of adult patients with newly diagnosed multiple myeloma who have undergone autologous stem cell transplantation. REVLIMID® is the first and only licensed maintenance treatment available to these patients. [Celgene International Sà rl] Press Release | |
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POLICY NEWSTrump’s 2018 Budget Will Squeeze Civilian Science Agencies The chunk of the federal budget that includes most of the U.S. government’s spending on basic science would shrink by 10.5% in 2018 under a plan outlined by President Donald Trump and administration officials. [ScienceInsider] Editorial Departing Senior NSF Manager Offers Hopeful Assessment of Agency’s Future The top aide to National Science Foundation (NSF) Director France Córdova has returned to his university after failing to win confirmation as deputy NSF director. But engineer Richard Buckius says his departure, less than a week after President Donald Trump took office, was long in the cards and not a political statement. [ScienceInsider] Editorial
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EVENTSNEW Keystone Symposium: mRNA Processing and Human Disease (C3) NEW Stem Cells in Drug Discovery Visit our events page to see a complete list of events in the community.
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JOB OPPORTUNITIESNEW Postdoctoral Fellow – Stem Cell and Leukemia Program (City of Hope) Postdoctoral Fellow – Human Genome Editing (Johns Hopkins University School of Medicine) Principal Scientist – Translational Development, Myeloid Disease Strategy (Celgene Corporation) Senior Scientist – Translational and Diagnostic Informatics (Celgene Corporation) Postdoctoral Position – Leukemia Research (Department of Biomedicine, University Hospital Basel) Tenure Track Faculty – Stem Cells and Regenerative Medicine (University of Notre Dame) Research Specialist – Metabolomics Methods to Stem Cell Metabolism (Howard Hughes Medical Institute) Principal Scientist – Translational Development (Celgene Corporation) Associate Director – Translational Development (Celgene Corporation) Assistant Professor – Molecular Therapeutics of Cancer (Dartmouth College) Postdoctoral Fellow – Hematopoietic Development and Homeostasis (Harvard Medical School, BIDMC) Recruit Top Talent: Reach potential candidates by posting your organization’s career opportunities on the Connexon Creative Job Board at no cost.
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Home Hematopoiesis News Volume 8.08 | Feb 28 2017