Hematopoiesis News Volume 8.21 | May 30 2017

TOP STORY

Atypical Chemokine Receptor 1 on Nucleated Erythroid Cells Regulates Hematopoiesis

Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Researchers describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia. [Nat Immunol] Abstract

(Ranked by impact factor of the journal)

Aryl Hydrocarbon Receptor Inhibition Promotes Hemato-Lymphoid Development from Human Pluripotent Stem Cells

To model hematopoiesis, human embryonic stem cells (hESCs) were allowed to differentiate in defined conditions in the presence of the aryl hydrocarbon receptor (AHR) antagonist stemreginin-1 (SR-1) or AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin. Scientists demonstrated a significant increase in CD34⁺CD31⁺ hemato-endothelial cells in SR-1 treated hESCs, as well as a two-fold expansion of CD34⁺CD45⁺ hematopoietic progenitor cells. [Blood] Abstract

Engineering the Hemogenic Niche Mitigates Endogenous Inhibitory Signals and Controls Pluripotent Stem Cell-Derived Blood Emergence

Efforts to recapitulate hematopoiesis, a process guided by spatial and temporal inductive signals, to generate hematopoietic progenitors from human pluripotent stem cells (hPSCs) have focused primarily on exogenous signaling pathway activation or inhibition. The authors showed that hemogenic niches can be engineered using microfabrication strategies by micropatterning hPSC-derived hemogenic endothelial cells into spatially-organized, size-controlled colonies. [Nat Commun] Full Article | Press Release

Lymphoid Differentiation of Hematopoietic Stem Cells Requires Efficient Cxcr4 Desensitization

Using a mouse model with a naturally occurring WHIM syndrome (WS)-linked gain-of-function Cxcr4 mutation, scientists explored the possibility that the lymphopenia in WS arises from defects at the hematopoietic stem and progenitor cell level. They report that Cxcr4 desensitization was required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. [J Exp Med] Abstract

Combined Influence of Biophysical and Biochemical Cues on Maintenance and Proliferation of Hematopoietic Stem Cells

Investigators employed a modular, glycosaminoglycan-based biohybrid hydrogel system to balance proliferation of human hematopoietic stem and progenitor cells (HSPCs) and maintenance of quiescent hematopoietic stem cells through simultaneous regulation of exogenous biochemical and biophysical cues. Their results demonstrated that HSPCs respond to increased spatial confinement with lowered proliferation and cell cycling, which resulted in a higher frequency of quiescent long-term culture initiating cells. [Biomaterials] Abstract

Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

Researchers present in vivo genetic evidence showing that WHS candidate 1 (Whsc1) plays an important role at several points of hematopoietic development. Their results demonstrated that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness, and proliferation. [Cell Rep] Full Article | Graphical Abstract

Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment

Using single-cell transcriptomics, the authors identified a distinct subpopulation of old hematopoietic stem cells (HSCs) carrying a p53 signature indicative of stem cell decline alongside pro-proliferative JAK/STAT signaling. Their results revealed cellular heterogeneity in the onset of HSC aging and implicate a role for JAK2V617F-driven proliferation in the p53-mediated functional decline of old HSCs. [Cell Rep] Full Article | Graphical Abstract

Reduced Hematopoietic Stem Cells Frequency Predicts Outcome in Acute Myeloid Leukemia

By relating hematopoietic stem cell frequencies to outcome, researchers detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients that achieved durable remissions. [Haematologica] Full Article

Inhibition of SDF-1 Receptors CXCR4 and CXCR7 Attenuates Acute Pulmonary Inflammation via the Adenosine A_2B-Receptor on Blood Cells

Researchers investigated the role of CXCR4- and CXCR7-inhibition and the potential link to the adenosine A_2B-receptor, which plays an important anti-inflammatory role in the lung. After LPS-inhalation for 45 minutes, administration of the CXCR4-inhibitor decreased transendothelial and transepithelial migration, whereas CXCR7-antagonism influenced epithelial migration exclusively. [Cell Death Dis] Full Article

Global Increase in Replication Fork Speed during a p57^KIP2-Regulated Erythroid Cell Fate Switch

Scientists studied an S phase–dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. They found that progenitors are dependent on p57^KIP2-mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase inhibitors. [Sci Adv] Full Article

CLINICAL RESEARCH

HHV-6 Reactivation as a Cause of Fever in Autologous Hematopoietic Stem Cell Transplant Recipients

The authors retrospectively reviewed clinical, biological, radiological, treatment and outcomes of patients with positive HHV-6 DNA in whole blood following autologous hematopoietic stem cell transplantation. They report the biological and clinical impacts possibly associated with HHV-6 reactivation in autologous hematopoietic stem cell transplant recipients after intensive chemotherapy regimen for lymphoma. [J Infect] Abstract

Preventing Relapse after Hematopoietic Stem Cell Transplantation for Acute Leukemia: The Role of Post-Transplantation Minimal Residual Disease (MRD) Monitoring and MRD-Directed Intervention

Referring to the issues of whether and who would benefit from pre-emptive intervention according to MRD, scientists summarize the rapidly evolving area of MRD monitoring and MRD-directed interventions in acute leukemia patients after allogeneic hematopoietic stem cell transplantation. [Br J Haematol] Abstract

The Cytokine Flt3-Ligand in Normal and Malignant Hematopoiesis

The authors provide an overview of the current knowledge on the role of Fms-like tyrosine kinase 3 ligand in the generation of blood cell lineages. They examine recent studies on Flt3 expression by hematopoietic stem cells and its potential instructive action at early stages of hematopoiesis. In addition, they review current findings on the role of mutated FLT3 in leukemia and the development of FLT3 inhibitors for therapeutic use to treat acute myeloid leukemia. [Int J Mol Sci] Full Article

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

Asana BioSciences Initiates Phase II Evaluation of ASN002, a Novel SYK/JAK Inhibitor, in NHL, CLL and MF Updated Clinical Data to Be Presented

Asana BioSciences, LLC announced that one of its lead molecules, ASN002, has completed the dose escalation phase in patients with non-Hodgkin’s lymphoma (NHL) and is now being investigated in the Phase II part of a multicenter trial in multiple hematological indications including NHL, chronic lymphocytic leukemia (CLL), and myelofibrosis (MF). [Press release from Asana BioSciences, LLC discussing research to be presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago] Press Release

Partnership Announced with Dana-Farber Cancer Institute and the Leukemia & Lymphoma Society to Offer Innovative Blood Cancer Clinical Trials

The University of Kansas Cancer Center has announced that it will join a consortium with the Dana-Farber Cancer Institute, in collaboration with The Leukemia & Lymphoma Society, to bring clinical trials testing innovative blood cancer therapies to Kansas City. [University of Kansas Cancer Center] Press Release

Kite Receives U.S. Food and Drug Administration Priority Review for Axicabtagene Ciloleucel

Kite Pharma, Inc. announced that the U.S. Food and Drug Administration has accepted for priority review the Biologics License Application for axicabtagene ciloleucel. The submission follows positive data demonstrated with a single infusion of axicabtagene ciloleucel in the ZUMA-1 Phase II trial in patients with refractory aggressive non-Hodgkin lymphoma. [Kite Pharma, Inc.] Press Release

Aprea Therapeutics Announces First Patients Enrolled in Phase Ib/II Clinical Study of APR-246 for the Treatment of Myelodysplastic Syndrome

Aprea Therapeutics announced that the first patient was enrolled in the Phase Ib/II clinical study of APR-246 in myelodysplastic syndrome (MDS). The study, sponsored by the Moffitt Cancer Center with financial support from the Evans MDS Clinical Research Consortium and the MDS foundation, will evaluate APR-246 in combination with azacitadine for the treatment of TP53 mutant MDS. [Aprea Therapeutics] Press Release

Xenetic Biosciences Receives Program Update from Partner Shire’s Phase I/II Study Evaluating SHP656 in Development as a Long-Acting Treatment for Hemophilia A

Xenetic Biosciences, Inc. announced that it has received an update on the Phase I/II clinical study conducted by its partner Shire, evaluating SHP656, which is being developed as a long-acting therapeutic for the treatment of hemophilia A utilizing Xenetic’s PolyXen^™ platform technology to conjugate polysialic acid to therapeutic blood-clotting factors. [Xenetic Biosciences, Inc.] Press Release

Phase I Safety Study Supports Planned Development of PCM-075 in AML

Trovagene, Inc. announced summary data from a Phase I safety study conducted by Nerviano Medical Sciences with PCM-075, a polo-like kinase 1 inhibitor. This data is supportive of a planned Phase I/II clinical trial in patients with acute myeloid leukemia (AML) and is now being submitted for peer review publication by study investigators. [Trovagene, Inc.] Press Release

FDA Advisory Committee Recommends Approval of Pfizer’s Proposed Biosimilar to Epogen^®/Procrit^® across All Indications

Pfizer Inc. announced the United States (U.S.) Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee recommended approval of the company’s proposed epoetin alfa biosimilar across all indications. This marks the first time a biosimilar erythropoiesis-stimulating agent has been recommended for approval by a U.S. FDA Advisory Committee. [Pfizer Inc.] Press Release

GlycoMimetics’ GMI-1271 Receives EU Orphan Drug Designation for Acute Myeloid Leukemia

GlycoMimetics, Inc. announced that the European Commission, based on a favorable recommendation from the European Medicines Agency Committee for Orphan Medicinal Products, has granted orphan designation for the company’s drug candidate GMI-1271 for the treatment of acute myeloid leukemia. [GlycoMimetics, Inc.] Press Release

Actinium Pharmaceuticals Granted Orphan Designation from the European Medicines Agency for Actimab-A

Actinium Pharmaceuticals, Inc. announced that Actimab-A has been granted orphan designation in the European Union by the European Medicines Agency. Actimab-A is intended to be used, upon approval, in patients newly diagnosed with acute myeloid leukemia who are over the age of 60 that are ineligible for standard induction therapy. [Actinium Pharmaceuticals, Inc.] Press Release

Texas on Track to Become First State to Explicitly Back Stem Cell Therapies

Lawmakers in Austin have approved a bill authorizing unapproved stem cell therapies, putting Texas on track to become the first state to explicitly recognize the experimental treatments. [STAT News] Editorial

NIH Scales Back Plan to Curb Support for Big Labs after Hearing Concerns

Faced with a barrage of criticism, the National Institutes of Health (NIH) has scaled back a plan to cap its support for individual labs in order to free up funds for more scientists. The changes did not appease scientists who gave NIH a tongue-lashing at a meeting of NIH’s Council of Councils. [ScienceInsider] Editorial

House Science Panel Joins Trump in Questioning Research Overhead Payments

A hearing on how the U.S. government defrays the cost of doing federally funded research on college campuses might put most people to sleep. But when budgets are tight, the billions of dollars being spent each year on so-called overhead become an irresistible target for lawmakers. [ScienceInsider] Editorial

NEW Drug Discovery & Therapy World Congress 2017
July 10-13, 2017
Boston, United States

NEW Applications of the Hematopoietic Progenitor Assay Training Course
October 11-13, 2017
Vancouver, Canada

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

NEW Postdoctoral Fellow – Stem Cell Biology and Epigenetics (University of South Carolina)

Postdoctoral Fellow – Single Cell Sequencing (University of British Columbia Mechanical Engineering)

Postdoctoral Fellow – Hematopoietic Chimeras (Children’s Hospital of Chicago and Northwestern University)

Full Member Faculty – Hematopoietic Cell Transplant Program (Fred Hutchinson Cancer Research Center)

Senior Research Scientist – Hematopoietic Stem Cells (Texas Tech University Health Sciences Center El Paso)

Faculty Position – Normal and Malignant Hematopoiesis (Cincinnati Children’s Hospital)

Postdoctoral Position – Experimental Leukemia Research (University Children’s Hospital Basel)

Postdoctoral Position – Hematopoietic Stem/Progenitor Cell Research (Frederick National Laboratory for Cancer/National Cancer Institute)

Principal Investigator – Hematopoietic and Immune System (Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases)

Senior Research Associate – Hematopoietic and Immune System (Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases)

Postdoctoral Position – Leukemia Research (VIB-KU Leuven Center for Cancer Biology)

Lab Director – Pharmacokinetics (Seattle Cancer Care Alliance)

Principal Scientist – Immuno Oncology (Celgene Corporation)

Postdoctoral Fellow – Age Associated Changes of the Hematopoietic Stem Cell Compartment (National Institutes of Health/National Institute on Aging)

Associate Director – Translational Development (Celgene Corporation)

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