Hematopoiesis News Volume 10.22 | Jun 11 2019

TOP STORY

Harnessing Hematopoietic Stem Cell Low Intracellular Calcium Improves Their Maintenance In Vitro

Scientists discovered that culturing of HSCs in low calcium increased their maintenance as determined by phenotype, function, and single-cell expression signature. Low-calcium conditions inhibited calpain proteases, which targeted ten-eleven translocated (TET) enzymes, of which TET2 was required for the effect of low calcium conditions on HSC maintenance in vitro. [Cell Stem Cell] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

Non-Oncogene Addiction to SIRT3 Plays a Critical Role in Lymphomagenesis

Investigators showed that diffuse large B cell lymphomas were dependent on mitochondrial lysine deacetylase SIRT3 for proliferation, survival, self-renewal, and tumor growth in vivo regardless of disease subtype and genetics. SIRT3 knockout attenuated B cell lymphomagenesis in VavP-Bcl2 mice without affecting normal germinal center formation. [Cancer Cell] Abstract | Graphical Abstract

SIRT1 Regulates Metabolism and Leukemogenic Potential in CML Stem Cells

Researchers identified a previously unrecognized role for sirtuin 1 (SIRT1) in mediating increased mitochondrial oxidative phosphorylation in chronic myeloid leukemia (CML) leukemia stem cells. They showed that mitochondrial alterations were kinase independent and that tyrosine kinase inhibitor treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. [J Clin Invest] Full Article | Press Release | Graphical Abstract

RUNX3 Levels in Human Hematopoietic Progenitors Are Regulated by Aging and Dictate Erythroid-Myeloid Balance

Knockdown studies revealed human hematopoietic stem and progenitor cells to be strongly influenced by RUNX3 levels, with modest deficiencies abrogating erythroid differentiation at multiple steps while retaining capacity for granulopoiesis. Transcriptome profiling indicated control by RUNX3 of key erythroid transcription factors, including KLF1 and GATA1. [Haematologica] Abstract

Latexin Regulation by HMGB2 Is Required for Hematopoietic Stem Cell Maintenance

High-mobility group protein B2 knockdown increased latexin expression at transcript and protein levels, and decreased HSC number and regeneration capacity in vivo. Concomitant blockage of latexin activation significantly reversed these phenotypic changes, suggesting that latexin was one of the downstream targets and functional mediators of high-mobility group protein B2. [Haematologica] Abstract

Transcriptional States and Chromatin Accessibility Underlying Human Erythropoiesis

Researchers applied deep transcriptomic and accessible chromatin profiling to characterize a faithful ex vivo human erythroid differentiation system from hematopoietic stem and progenitor cells. They revealed stage-specific transcriptional states and chromatin accessibility during various stages of erythropoiesis, including 14,260 differentially expressed genes and 63,659 variably accessible chromatin peaks. [Cell Rep] Full Article | Graphical Abstract

Overexpression of GATA2 Enhances Development and Maintenance of Human Embryonic Stem Cell-Derived Hematopoietic Stem Cell-Like Progenitors

GATA2 promoted expansion of hemogenic precursors via the endothelial-to-hematopoietic transition and then helped to maintain hematopoietic stem (HS)-like cells in a quiescent state by regulating cell cycle. RNA sequencing showed that human pluripotent stem cell-derived HS-like cells were very similar to human fetal liver-derived HSCs. [Stem Cell Reports] Full Article | Graphical Abstract

In Vivo Outcome of Homology-Directed Repair at the HBB Gene in HSC Using Alternative Donor Template Delivery Methods

The authors directly compared the relative efficiency of co-delivery of a novel CRISPR/Cas9 ribonucleoprotein targeting HBB in association with recombinant adeno-associated virus 6 vs. single-stranded oligodeoxynucleotides to introduce the sickle mutation or a silent change in human CD34⁺ mobilized peripheral blood stem cells derived from healthy donors. [Mol Ther Nucleic Acids] Abstract | Full Article

CLINICAL RESEARCH

The Neuropeptide Receptor Calcitonin Receptor-Like (CALCRL) Is a Potential Therapeutic Target in Acute Myeloid Leukemia

Investigators characterized the role of CALCRL in acute myeloid leukemia (AML). They analyzed CALCRL expression in collectively more than 1500 well-characterized AML patients from five international cohorts and evaluated associations with survival. [Leukemia] Abstract

Use of TCR α⁺β⁺/CD19⁺-Depleted Haploidentical Hematopoietic Stem Cell Transplant Is a Viable Option in Patients with Primary Immune Deficiency without Matched Sibling Donor

Scientists evaluated outcomes of T cell receptor α⁺β⁺/CD19⁺-depleted haploidentical HSC transplantation (HSCT) in pediatric patients with primary immune deficiency at a single center in Australia. They evaluated immune reconstitution, looking at time to T cell and B cell reconstitution, and B cell function post-HSCT. Eleven patients with a mean age of 7.92 years were included. [J Clin Immunol] Abstract

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Somatic Genetic Rescue in Mendelian Hematopoietic Diseases

A growing number of studies of Mendelian hematopoietic disorders indicate that somatic genetic events can offset the pathogenic effect of germline mutations at the cellular level, leading to genetic mosaicism and, in some cases, resulting in a milder disease phenotype. [Nat Rev Genet] Abstract

Targeting the Tumor Microenvironment of Leukemia and Lymphoma

The authors dissect the stromal compartment in lymphoid organs, focusing on conditions that are prevalent in an autochthonous environment for lymphoid neoplasia. Identification of tumor-promoting factors is instrumental in the selection of therapeutic targets that are part of the immune system. [Trends Cancer] Abstract

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

Janssen to Present Data from Its Robust Oncology Portfolio and Pipeline

Janssen will present 28 company-sponsored abstracts from its leading hematological malignancy portfolio, including the latest results for DARZALEX^® and IMBRUVICA^®. [Press release from Janssen Global Services, LLC (Business Wire, Inc.) discussing research to be presented at the 24^th European Hematology Association (EHA) Annual Congress, Amsterdam] Press Release

ArQule to Present Clinical Data for Its BTK Inhibitor, ARQ 531

ArQule, Inc. announced that it will present clinical data from the company-sponsored Phase I dose escalation study on its BTK inhibitor, ARQ 531, for the treatment of relapsed or refractory B-cell lymphoid malignancies in a poster presentation. [Press release from ArQule, Inc. discussing research to be presented at the 24^th European Hematology Association (EHA) Annual Congress, Amsterdam] Press Release

Onconova Therapeutics Announces Presentations

Onconova Therapeutics, Inc. announced two presentations. Dr. Steven Fruchtman, President & CEO, Dr. Ric Woodman, CMO, and Dr. Ronnee Adesanya, VP Medical Affairs, will be attending the conference. [Press release from Onconova Therapeutics, Inc. discussing research to be presented at the 24^th European Hematology Association (EHA) Annual Congress, Amsterdam] Press Release

Achillion Announces Upcoming Scientific Presentation

Achillion Pharmaceuticals, Inc. announced that the final data set for ACH-4471 proof of concept Phase II trial in untreated patients with paroxysmal nocturnal hemoglobinuria was accepted for oral presentation. [Press release from Achillion Pharmaceuticals, Inc. discussing research to be presented at the 24^th European Hematology Association (EHA) Annual Congress, Amsterdam] Press Release

Taiho Oncology Announces Agreement with Otsuka to Commercialize Astex Pharmaceuticals’ Drug Candidates

Taiho Oncology, Inc. announced that it has assumed commercialization responsibility from Otsuka Pharmaceuticals Co., Ltd. for the novel fixed-dose combination of cedazuridine and decitabine and guadecitabine in the US and Canada, subject to regulatory approvals. Taiho Pharma Canada, Inc. will commercialize these compounds in Canada. [Taiho Oncology, Inc.] Press Release

Genmab Signs Agreement with Janssen for Next-Generation CD38 Antibody, HexaBody^®-CD38

Under the terms of the agreement, Genmab will collaborate exclusively with Janssen on HexaBody-CD38, with Genmab funding research and development activities until completion of clinical proof of concept studies in multiple myeloma and diffuse large B-cell lymphoma. [Genmab A/S] Press Release

Astex Pharmaceuticals and Otsuka Announce Results of the Phase III ASCERTAIN Study of the Novel Oral Cedazuridine and Decitabine Fixed-Dose Combination (ASTX727) in Patients with Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Astex Pharmaceuticals, Inc. and Otsuka Pharmaceutical Co. Ltd., announced top-line results from the ASCERTAIN Phase III study evaluating cedazuridine and decitabine fixed-dose combination vs decitabine IV in adults with intermediate and high-risk MDS or CMML. [Astex Pharmaceuticals, Inc.] Press Release

Innate Pharma Enrolls First Patient in IPH4102 TELLOMAK Phase II Study

Innate Pharma SA announced that it has enrolled the first patient in the TELLOMAK Phase II study of IPH4102 in patients with different subtypes of T-cell lymphoma (TCL). IPH4102 is Innate Pharma’s wholly-owned first-in-class anti-KIR3DL2 antibody, developed for the treatment of TCL. [Innate Pharma SA] Press Release

Xynomic Dosed First Patient in Phase I/II Lymphoma Trial

Xynomic Pharmaceuticals Holdings, Inc. announced that Xynomic has dosed the first patient in a Phase I/II trial that combines abexinostat with ibrutinib in patients with relapsed/refractory mantle cell lymphoma or relapsed/refractory diffuse large B-cell lymphoma at Memorial Sloan Kettering Cancer Center. [Xynomic Pharmaceuticals Holdings, Inc. (GlobeNewswire, Inc.)] Press Release

Cellenkos, Inc. Initiates Phase I Clinical Trial of CK0801 for Treatment of Bone Marrow Failure Syndromes

Cellenkos™ announced the initiation of a Phase I Clinical Trial of CK0801, a first-in-class, allogeneic cord blood-derived T-regulatory cell product, for treatment of patients with bone marrow failure syndromes, including aplastic anemia, hypoplastic myelodysplasia, and primary myelofibrosis. [Cellenkos™] Press Release

Pediatric CAR T-Cell Immunotherapy Trial Aims to Improve Remission Rates of Leukemia at Children’s National Health System

Children’s National Health System announced the opening of a unique chimeric antigen receptor (CAR) T-cell immunotherapy trial for pediatric patients with relapsed positive acute lymphoblastic leukemia. The PLAT-05 trial will focus on targeting the CD19 and CD22 proteins simultaneously found in leukemia cancer cells. [Children’s National Health System (PR Newswire Association LLC.)] Press Release

FDA Grants Genentech’s Polivy Accelerated Approval for People with Previously Treated Aggressive Lymphoma

Genentech announced that the FDA has granted accelerated approval to Polivy™ in combination with bendamustine plus Rituxan^® for the treatment of adults with relapsed or refractory diffuse large B-cell lymphoma, who have received at least two prior therapies. [Genentech, Inc.] Press Release

Sierra Announces Momelotinib Granted FDA Fast Track Designation

Sierra Oncology, Inc. announced that the FDA has granted Fast Track designation to momelotinib, a JAK1, JAK2 and ACVR1 inhibitor, for the treatment of patients with intermediate/high-risk myelofibrosis who have previously received a JAK inhibitor. [Sierra Oncology, Inc.] Press Release

TG Therapeutics Confirms Registration Path for Umbralisib in Marginal Zone Lymphoma Following FDA Meeting

TG Therapeutics, Inc. announced that the company has confirmed its path to submit umbralisib for accelerated approval based on data from the marginal zone lymphoma (MZL) cohort of the UNITY-NHL Phase IIb trial. The company recently had a productive Breakthrough Therapy Designation meeting with the FDA to discuss the MZL submission strategy. [TG Therapeutics, Inc.] Press Release

Sudanese Academics Defiant as Revolution Turns Bloody

Sudan’s universities are shut, flights have been suspended and the Internet remains almost entirely blocked after a brutal crackdown in which paramilitaries are thought to have killed some 100 pro-democracy protestors. But none of this has dented the resolve of the protestors, whose ranks include several prominent academics and whose demands include freeing universities from government influence. [Nature News] Editorial

Wellcome Sanger Institute to Close Animal Facility

The Wellcome Sanger Institute announced that it would be closing its animal facility, which provides mice, zebrafish, rats, and frogs to geneticists at the institute and internationally, reports Nature. The institute states that the closure is related to the growing use of cell lines and organoids, instead of animals. [The Scientist] Editorial

Stem Cell Clinics Co-Opt Clinical-Trials Registry to Market Unproven Therapies, Critics Say

On the one hand, the FDA issued a letter stating that what an Arizona distributor was selling as stem cell therapies were “unapproved” and posed “safety concerns.” On the other, a National Institutes of Health database — clinicaltrials.gov — went right on listing the same merchant’s studies, with a link to the company’s website and the word “Recruiting” displayed invitingly in green. [STAT News] Editorial

NEW Keystone Symposia: Tumor Metabolism
March 8-12, 2020
Banff, Alberta, Canada

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NEW Senior Lecturer Positions – Clinical Oncology or Hematology (Karolinska Institutet)

Research Fellow – Hematology, Blood-Disorders & Stem Cell Biology (New York Blood Center)

Researcher – Clonal Hematopoiesis & Molecular Epidemiology (Uppsala University)

Postdoctoral Scholar – Pediatric Hematology/Oncology (Pennsylvania State University)

Postdoctoral Scientist – Hematopoietic Stem Cell Research (DKFZ / HI-STEM)

Postdoctoral Scientist – Inflammatory Stress in the Bone Marrow (DKFZ / HI-STEM)

Postdoctoral Fellow – Molecular Mechanisms of Myeloma (City of Hope)

Postdoctoral Research Fellow – Translational Gene Therapy & Hematopoietic Stem Cell Research (Fred Hutchinson Cancer Research Center)

Postdoctoral Position – Stem Cell Transplantation Cell Interaction (University of Illinois at Chicago)

Assistant Professor – Lymphoma/Myeloma Research (The University of Texas MD Anderson Cancer Center)

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