Hematopoiesis News Volume 8.17 | May 2 2017

TOP STORY

Transient CDK4/6 Inhibition Protects Hematopoietic Stem Cells from Chemotherapy-Induced Exhaustion

Serial exposure to cytotoxics causes a long-term hematopoietic compromise (“exhaustion”), which limits the use of chemotherapy and success of cancer therapy. Scientists showed that the coadministration of G1T28, which is a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), contemporaneously with cytotoxic chemotherapy protects murine hematopoietic stem cells from chemotherapy-induced exhaustion in a serial 5-fluorouracil treatment model. [Sci Transl Med] Abstract

(Ranked by impact factor of the journal)

Tet2 Loss Leads to Hypermutagenicity in Hematopoietic Stem/Progenitor Cells

Although TET2 mutations frequently occur in various types of hematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. The authors showed that Tet2^−/− mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. [Nat Commun] Full Article | Press Release

MYB–GATA1 Fusion Promotes Basophilic Leukemia: Involvement of IL33 and Nerve Growth Factor Receptors

A recurrent t(X;6)(p11;q23) translocation generating a MYB–GATA1 fusion gene in male infants with acute basophilic leukemia was previously described. To better understand its role, the chimeric MYB-GATA1 transcription factor was expressed in CD34-positive hematopoietic progenitors which were transplanted into immunodeficient mice. Cells expressing MYB-GATA1 showed increased expression of markers of immaturity, of granulocytic lineage and of basophilic differentiation. [J Pathol] Abstract

CRISPR/Cas9-Directed Reassignment of the GATA1 Initiation Codon in K562 Cells to Recapitulate AML in Down Syndrome

Using a CRISPR/Cas9 system, investigators reengineered a translational start site in the GATA1 gene in K562 cells. This mutation accounts largely for the onset of myeloid leukemia in Down syndrome (ML-DS). They utilized CRISPR/Cas9 to generate mammalian cell lines that express truncated versions of the Gata1s protein similar to that seen in ML-DS, as determined by analyzing specific genetic alterations resulting from CRISPR/Cas9 cleavage. [Mol Ther Nucleic Acids] Full Article

3-Aroyl-1,4-Diarylpyrroles Inhibit Chronic Myeloid Leukemia Cell Growth through an Interaction with Tubulin

Researchers designed 3-aroyl-1,4-diarylpyrrole (ARDAP) derivatives as potential anticancer agents having different substituents at the 1- or 4-phenyl ring. ARDAP compounds exhibited potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. [ACS Med Chem Lett] Abstract | Graphical Abstract

Impact of the c–Myb^E308G Mutation on Mouse Myelopoiesis and Dendritic Cell Development

Booreana mice carrying the c–Myb^E308G point mutation were analyzed to determine changes in early hematopoiesis in the bone marrow and among mature cells in the periphery. This point mutation led to increased numbers of early hematopoietic stem and progenitor cells, with a subsequent reduction in the development of B cells, erythroid cells, and neutrophils, and increased numbers of myeloid cells and granulocytes. [PLoS One] Full Article

BLOS2 Maintains Hematopoietic Stem Cells in the Fetal Liver via Repressing Notch Signaling

It was recently reported that the endolysosomal trafficking factor BLOS2, encoded by the Bloc1s2 gene, regulates hematopoietic stem cell (HSC) emergence in the aorta-gonad-mesonephros region; however, whether it plays a role in the fetal liver (FL) remains unknown. The authors showed that BLOS2 plays an essential role in regulation of HSC proliferation and differentiation in the FL. Bloc1s2 depletion lead to elevated Notch signaling, with an increased frequency but weakened self-renewal ability of FL HSCs. [Exp Hematol] Abstract

CLINICAL RESEARCH

Comparing Outcomes of Matched Related Donor and Matched Unrelated Donor Hematopoietic Cell Transplants in Adults with B-Cell Acute Lymphoblastic Leukemia

Post-hematopoietic cell transplantation outcomes for 1458 acute lymphoblastic leukemia patients from 2000 to 2011 were analyzed, and related donor (RD) and unrelated donor (URD) transplants were compared. In the absence of RD transplantation, 8/8 URD transplantation was a viable alternative with similar survival outcomes, whereas 7/8 URD transplantation was associated with poorer overall survival. [Cancer] Abstract

Earlier Defibrotide Initiation Post-Diagnosis of Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome Improves Day +100 Survival following Hematopoietic Stem Cell Transplantation

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for hematopoietic stem cell transplant (HSCT). Data from this study were examined post–hoc to determine if the timing of defibrotide initiation post-VOD/SOS diagnosis affected day +100 survival post-HSCT. [Br J Haematol] Abstract | Full Article

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Abnormalities of the Short Arm of Chromosome 17

Scientists retrospectively analyzed a Japanese nationwide database to elucidate the impact of abnormalities in the short arm of chromosome 17 (abnl[17p]) on the outcomes of allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia. Among the abnl(17p) patients, male sex, non-remission disease status at transplantation and poor cytogenetic risk group were significantly associated with shorter overall survival. [Biol Blood Marrow Transplant] Abstract

TET Family Dioxygenases and DNA Demethylation in Stem Cells and Cancers

Ten-eleven translocation (TET) loss-of-function is causally related to the onset and progression of hematologic malignancy in vivo. The authors focus on recent advances in the mechanistic understanding of DNA methylation–demethylation dynamics, and their potential regulatory functions in cellular differentiation and oncogenic transformation. [Exp Mol Med] Full Article

Creating Artificial Lymphoid Tissues to Study Immunity and Hematological Malignancies

New bone marrow and lymph node models have been created to, respectively, study microenvironmental interactions in hematopoiesis and germinal center-like biology. These models have also been extended to understand the effect of these interactions on the progression and therapeutic response in leukemia, multiple myeloma, and lymphoma. [Curr Opin Hematol] Abstract

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Be The Match BioTherapies Announces Collaboration Agreement with Magenta Therapeutics

Be The Match BioTherapies^SM announced that it has entered into a strategic partnership with Magenta Therapeutics. The collaboration is intended to support efforts to improve transplant outcomes and expand the application of stem cell transplantation into disease indications that include autoimmunity, serious inherited immune and metabolic disorders, blood defects and blood cancers. [Be The Match BioTherapies^SM] Press Release

Novartis Receives FDA Approval for Rydapt^® in Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML) and Three Types of Systemic Mastocytosis (SM)

Novartis announced the US Food and Drug Administration (FDA) has approved Rydapt^® for two indications. The first indication is for the treatment of AML in newly diagnosed patients who are FMS-like tyrosine kinase 3 mutation-positive (FLT3⁺), as detected by an FDA-approved test, in combination with chemotherapy. Rydapt is also approved to treat adults with advanced SM, which includes aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm and mast cell leukemia. [Novartis] Press Release

Kiadis Pharma Announces Filing of Marketing Authorization with the European Medicines Agency for ATIR101^™ in Blood Cancers

Kiadis Pharma N.V. announced it has submitted a Marketing Authorization Application to the European Medicines Agency for its lead product, ATIR101^™. The company is seeking marketing approval in the European Union for ATIR101^™ as an adjunctive treatment in hematopoietic stem cell transplantation for malignant disease. [Kiadis Pharma N.V.] Press Release

First FDA-Approved 100 mg Thiotepa Now Available through Amneal Biosciences as TEPADINA^® (Thiotepa) for Injection

Thiotepa is now available through Amneal Biosciences in both 100 mg/vial and 15 mg/vial as branded TEPADINA^® for injection. TEPADINA^® is approved to reduce the risk of graft rejection when used in conjunction with high-dose busulfan and cyclophosphamide as a preparative regimen for allogeneic hematopoietic stem cell transplantation for pediatric patients with class 3 beta-thalassemia. [Amneal Biosciences (PR Newswire Association LLC.)] Press Release

Researchers Frustrated by Italian Misconduct Probe

More than five years ago, Italian police began investigating allegations of research misconduct in papers by Alfredo Fusco, a prominent cancer scientist in Naples. Researchers frustrated by the case’s slow progress have told Nature that there is strong evidence that dozens of papers may contain manipulated data — and that a commercial photography studio was called in to cut and paste images. They say they are speaking out about the magnitude of the allegations because of their increasing impatience with the slow pace of investigations by police and by academic authorities. [Nature News] Editorial

How Science Fares in the U.S. Budget Deal

Congress has finally reached a deal on spending bills for the 2017 fiscal year. House of Representatives and Senate leaders announced that they expect lawmakers to vote on an agreement that wraps together all 12 appropriations bills that fund federal operations. For the past seven months, the government has been operating under a continuing resolution that froze 2017 spending at most agencies at 2016 levels and generally prevented them from starting new programs. [ScienceInsider] Editorial

NEW Standardization of the Hematopoietic Progenitor Assay Training Course
June 20-21, 2017
Cambridge, United Kingdom

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

NEW Research Associate – Blood Stem Cells (University of Cambridge)

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

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

Postdoctoral Position – Acute Myeloid Leukemia (German Cancer Research Center)

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

Postdoctoral Position – Regulation of HSCs by Niche Cells (Universitätsklinikum Carl Gustav Carus Dresden)

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)

Scientist – Biological Function of Hematopoietic Stem Cells/Progenitors (HemoGenyx LLC)

Lab Director – Pharmacokinetics (Seattle Cancer Care Alliance)

Postdoctoral Positions – Gene Regulation, Epigenetics and/or Cancer Biology (The University of North Carolina at Chapel Hill)

Postdoctoral Fellow – Changes in Hematopoietic Stem Cell Biology (Lund University)

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)

Postdoctoral Fellow – Hematopoietic Development and Homeostasis (Harvard Medical School, BIDMC)

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