Hematopoiesis News Volume 10.14 | Apr 16 2019

TOP STORY

The Bone Marrow Microenvironment at Single-Cell Resolution

Scientists revealed previously unappreciated levels of cellular heterogeneity within the bone marrow niche and resolved cellular sources of pro-hematopoietic growth factors, chemokines and membrane-bound ligands. They observed that vascular Notch delta-like ligands were downregulated. In the absence of vascular Dll4, hematopoietic stem cells prematurely induced a myeloid transcriptional program. [Nature] Abstract

(Ranked by impact factor of the journal)

Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia

Investigators developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO’s N⁶-methyladenosine demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppressed proliferation and promoted the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. [Cancer Cell] Abstract | Graphical Abstract

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias

Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins, which inhibited glycogen synthase kinase 3-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. [Cancer Cell] Abstract | Graphical Abstract

Engineering a Hematopoietic Stem Cell Niche by Revitalizing Mesenchymal Stromal Cells

Researchers identified five genes encoding transcription factors that restored HSC niche function in cultured bone marrow-derived mesenchymal-derived stromal cells (MSCs). These revitalized MSCs exhibited enhanced synthesis of HSC niche factors while retaining their mesenchymal differentiation capacity. [Nat Cell Biol] Abstract

Regulation of Gene Expression by miR-144/451 during Mouse Erythropoiesis

To comprehensively and accurately identify erythroid miR-144/451 target mRNAs, scientists compared gene knockout and wild-type fetal liver erythroblasts by RNA-sequencing, quantitative proteomics and RNA immunoprecipitation of argonaute, a component of the RNA induced silencing complex that binds miRNAs complexed to their target mRNAs. [Blood] Abstract

Lineage-Specific RUNX2 Super-Enhancer Activates MYC and Promotes the Development of Blastic Plasmacytoid Dendritic Cell Neoplasm

RUNX2 ensured the expression of plasmacytoid dendritic cell (pDC)-signature genes in leukemic cells, but also confered survival and proliferative properties in blastic plasmacytoid dendritic cell neoplasm (BPDCN) cells. Furthermore, the pDC-specific RUNX2 super-enhancer was hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. [Nat Commun] Full Article

Cell-Intrinsic Depletion of Aml1-ETO-Expressing Pre-Leukemic Hematopoietic Stem Cells by K-Ras Activating Mutation

In the absence of activated Ras, Aml1-ETO-expressing hematopoietic stem cells conferred a competitive advantage. However, activated K-Ras had a marked detrimental effect on Aml1-ETO-expressing hematopoietic stem cells, leading to loss of both phenotypic and functional hematopoietic stem cells. [Haematologica] Abstract | Full Article

CLINICAL RESEARCH

Lentiviral Hemopoietic Stem/Progenitor Cell Gene Therapy for Treatment of Wiskott-Aldrich Syndrome: Interim Results of a Non-Randomized, Open-Label, Phase I/II Clinical Study

After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34⁺ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into hemopoietic stem/progenitor cells. [Lancet Haematol] Full Article

Monitoring Tumor Burden and Therapeutic Response through Analysis of Circulating Tumor DNA and Extracellular RNA in Multiple Myeloma Patients

A decrease in cell-free tumor DNA levels at day five of cycle one of treatment correlated with superior progression-free survival. Evaluation of extracellular RNA transcripts of candidate biomarkers indicated that high CRBN levels coupled with low levels of SPARC at baseline were associated with shorter overall survival. [Leukemia] Abstract

The Effects of Erythropoiesis-Stimulating Agents on the Management of Chemotherapy-Induced Anemia and Tumor Growth in Diffuse Large B-Cell Lymphoma Patients

The clinical study enrolled 50 histologically-confirmed diffuse large B-cell lymphoma patients receiving rituximab/cyclophosphamide/doxorubicin/vincristine/prednisolone (R-CHOP) who had hemoglobin levels <10.0 g/dL after a maximum of three R-CHOP cycles and received ≥four doses of fixed-dose darbepoetin once every three weeks. [Int J Cancer] Abstract

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Targeting the Spleen as an Alternative Site for Hematopoiesis

In terms of harnessing the spleen as a site for hematopoiesis, here the remarkable regenerative capacity of the spleen is considered with a view to forming additional or ectopic spleen tissue through cell engraftment. [Bioessays] Abstract

The Role of Cell Adhesion in Hematopoiesis and Leukemogenesis

The cells of the bone marrow microenvironment are emerging as important contributors and regulators of normal hematopoiesis. This microenvironment is perturbed during leukemogenesis, and evidence points toward a bidirectional communication between leukemia cells and the normal cells of the bone marrow, mediated by direct cell-cell contact as well as soluble factors. [J Cell Physiol] Abstract

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

Eagle Pharmaceuticals, Inc. Expands Licensing Agreement for BENDEKA™ with Teva Pharmaceuticals International GmbH

Eagle Pharmaceuticals, Inc. announced that it has expanded its existing BENDEKA™ licensing agreement with Teva Pharmaceuticals International GmbH. BENDEKA was granted orphan drug designation by the FDA and is approved for the treatment of patients with chronic lymphocytic leukemia and for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. [Eagle Pharmaceuticals, Inc.] Press Release

Nordic Nanovector: Safety Review Committee Approves Advancing to Final Dosing Regimen in Phase I Trial of Betalutin^® in DLBCL

Nordic Nanovector ASA announced that the Safety Review Committee for the ongoing LYMRIT 37-05 clinical trial of single-administration Betalutin^® in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) not eligible for stem cell transplantation has now reviewed safety data from the first three cohorts of patients. [Nordic Nanovector ASA] Press Release

Innovation Pharmaceuticals Reports p53 Drug Candidate Therapeutic Potential Further Supported by Academic Research in Leukemias and in Combination with Cancer Immunotherapies

Innovation Pharmaceuticals reported recent academic and pre-clinical research further supports the therapeutic potential of Kevetrin, the company’s p53 drug candidate, in leukemias and in combination with cancer immunotherapies. Kevetrin has been successfully evaluated in a Phase I clinical trial in advanced solid tumors and a Phase IIa clinical trial in late-stage ovarian cancer. [Innovation Pharmaceuticals] Press Release

Multiple Myeloma Research Foundation (MMRF) Launches Innovative Fund to Accelerate New Myeloma Treatments

The MMRF announced that it is launching the Myeloma Investment Fund dedicated to advancing new therapies for patients. The fund, which leverages the MMRF’s assets and expertise, is an independent, self-sustaining vehicle, and is the first and largest fund specifically focused in multiple myeloma. [Multiple Myeloma Research Foundation (PR Newswire Association LLC.)] Press Release

Generium Launches First Biosimilar of Eculizumab; Becomes Fifth Marketed Product Using Selexis SUREtechnology Platform

Selexis SA and Generium JSC announced that a fifth Selexis SUREtechnology Platform™-generated biological product has been approved for marketing. The latest approved product is a biosimilar monoclonal antibody, eculizumab, indicated for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. [Selexis SA] Press Release

Viracta Receives Orphan Drug Designation from the US FDA for Its Lead Epigenetic Drug Candidate Nanatinostat for EBV-Associated Cancers

Viracta Therapeutics, Inc. announced that the FDA has granted Orphan Drug Designations to their Phase II drug candidate, nanatinostat, in combination with the antiviral valganciclovir, for the treatment of post-transplant lymphoproliferative disorder, plasmablastic lymphoma, and angioimmunoblastic T cell lymphoma. [Viracta Therapeutics, Inc.] Press Release

Aprea Therapeutics Receives FDA Fast Track Designation and Orphan Drug Designation for APR-246 for the Treatment of Myelodysplastic Syndromes (MDS)

Aprea Therapeutics announced that the FDA has granted Fast Track Designation to APR-246 for the treatment of patients with MDS having a TP53 mutation. In addition, the FDA has also granted Orphan Drug Designation to APR-246 for the treatment of MDS. [Aprea Therapeutics] Press Release

TG Therapeutics Receives Orphan Drug Designation for Umbralisib from the US Food and Drug Administration for the Treatment of Marginal Zone Lymphoma

TG Therapeutics, Inc. announced that the FDA granted Orphan Drug Designation to its phosphoinositide-3-kinase delta inhibitor, umbralisib, for the treatment of patients with all three types of marginal zone lymphoma (MZL): nodal, extranodal, and splenic MZL. [TG Therapeutics, Inc.] Press Release

CRISPR Therapeutics and Vertex Announce FDA Fast Track Designation for CTX001 for the Treatment of Beta Thalassemia

CRISPR Therapeutics and Vertex Pharmaceuticals Incorporated announced that the FDA has granted Fast Track Designation for CTX001 for the treatment of transfusion-dependent beta thalassemia. CTX001 is an investigational, autologous, gene-edited hematopoietic stem cell therapy for patients suffering from severe hemoglobinopathies. [CRISPR Therapeutics] Press Release

Innovative Cellular Therapeutics Announces Successful Completion of Pre-IND Meeting with FDA

Innovative Cellular Therapeutics (ICT) announced it has successfully completed a pre-IND (Investigational New Drug) meeting with the FDA. At the meeting, the FDA provided feedback regarding ICT’s planned initiation of clinical trials under a US IND for its lead CAR-T candidate, ICTCAR014, for the treatment of non-Hodgkin lymphoma. [Innovative Cellular Therapeutics Co., Ltd.] Press Release

Influential Senator Asks NSF for Data on Threat from Foreign Influences

The National Science Foundation (NSF) has joined the list of federal agencies that Senator Chuck Grassley has asked for explanations of how they are preventing foreign scientists from ripping off US taxpayers. [ScienceInsider] Editorial

Indonesian Mega-Science Agency in the Balance as Election Begins

Indonesians will vote in a national election that pits two old rivals against each other. The stakes are high for science. President Joko Widodo says that if he is re-elected, he will overhaul how much of the country’s research is organized and funded. The main opposition candidate has been silent on science so far. [Nature News] Editorial

NEW European CanCer Organisation (ECCO) 2019: European Cancer Summit
September 12-14, 2019
Brussels, Belgium

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

NEW Tenure Track Senior Investigator – Malignant Hematology (Northwestern University Feinberg School of Medicine)

Postdoctoral Fellows – Hematological Malignancies & Cancer Immunology (Fox Chase Cancer Center)

Postdoctoral Fellowship – Myeloma Research (University of Calgary)

Postdoctoral Position – Transcriptional Regulation in Leukemia (VIB KU Leuven)

Postdoctoral Fellow – Leukemia Cell Survival (City of Hope)

Postdoctoral Fellowship – Hematopoiesis, Leukemia & Bone Marrow Failure Syndromes (The University of Texas Southwestern)

Associate Scientist – Immuno-Oncology (HMH Center for Discovery & Innovation)

Postdoctoral Scientist – Lymphocyte/Leukemia Research (City of Hope)

Assistant Professor – Sarcoma or Skeletal Related Malignancies (University of California, Davis)

Faculty Positions – Hematology and Oncology (University of California, Davis)

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