Hematopoiesis News Volume 10.16 | Apr 30 2019

TOP STORY

A Recurrent Activating Missense Mutation in Waldenström Macroglobulinemia Affects the DNA Binding of the ETS Transcription Factor SPI1 and Enhances Proliferation

Researchers identified a recurrent somatic mutation in PU.1/SPI1 in Waldenstrom macroglobulinemia, a B-cell lymphoproliferative disorder. Mutant SPI1 binding at promoters activated gene-sets typically promoted by other ETS factors, resulting in enhanced proliferation and decreased terminal B-cell differentiation in model cell lines and primary samples. [Cancer Discov] Abstract

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Targeting the RNA m⁶A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

YTHDF2 decreased the half-life of diverse m⁶A transcripts that contributed to the overall integrity of leukemic stem cell (LSC) function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primed cells for apoptosis. Intriguingly, YTHDF2 was not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. [Cell Stem Cell] Full Article | Press Release | Graphical Abstract

Reprogramming Identifies Functionally Distinct Stages of Clonal Evolution in Myelodysplastic Syndromes

Scientists differentiated isogenic myelodysplastic syndrome-induced pluripotent stem cells harboring up to four successive clonal abnormalities recapitulating a progressive decrease in hematopoietic differentiation potential. SF3B1, in concert with epigenetic mutations, perturbed mitochondrial function leading to accumulation of damaged mitochondria during disease progression, resulting in apoptosis and ineffective erythropoiesis. [Blood] Abstract

RUNX1 Targeted Therapy for AML Expressing Somatic or Germline Mutation in RUNX1

The authors identified novel expression-mimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing germline mutant (mt) RUNX1. Additionally, the EMs cinobufagin, anisomycin and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germ-line mtRUNX1 from patients with AML as compared to HPCs from patients with familial platelet disorder, or normal untransformed HPCs. [Blood] Abstract

The Vascular Bone Marrow Niche Influences Outcome in Chronic Myeloid Leukemia via the E-Selectin-SCL/TAL1-CD44 Axis

Investigators showed that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolonged survival of mice with chronic myeloid leukemia via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1⁺ cells led to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and protooncogene Scl/Tal1 in leukemia-initiating cells. [Haematologica] Full Article

HRI Coordinates Translation Necessary for Protein Homeostasis and Mitochondrial Function in Erythropoiesis

The absence of HRI in iron deficiency elicited a prominent cytoplasmic unfolded protein response and impaired mitochondrial respiration. Importantly, ATF4 target genes were activated during iron deficiency to maintain mitochondrial function and enable erythroid differentiation. [eLife] Full Article

UM171 Expands Distinct Types of Myeloid and NK Progenitors from Human Pluripotent Stem Cells

The authors revealed that culture of human pluripotent stem cell-hematopoietic progenitors (HPs) in HSC expansion conditions in the presence of UM171 predominantly expanded HPs with a unique CD34⁺CD41a^loCD45⁺ phenotype that were enriched in granulocytic progenitors. [Sci Rep] Full Article

USP10 Modulates the SKP2/Bcr-Abl Axis via Stabilizing SKP2 in Chronic Myeloid Leukemia

Scientists showed that USP10 as a novel deubiquitinase of S-phase kinase-associated protein 2 (SKP2) amplified the activation of Bcr-Abl via mediating deubiquitination and stabilization of SKP2 in chronic myeloid leukemia (CML) cells. Moreover, inhibition of USP10 significantly suppressed the proliferation of both imatinib-sensitive and imatinib-resistant CML cells, which likely depends on SKP2 status. [Cell Discov] Full Article

CLINICAL RESEARCH

Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm

In this open-label, multicohort study, researchers assigned 47 patients with untreated or relapsed blastic plasmacytoid dendritic-cell neoplasm to receive an intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days one to five of each 21-day cycle. [N Engl J Med] Abstract | Press Release

Hematopoietic Stem Cell Transplant Effectively Rescues Lymphocyte Differentiation and Function in DOCK8-Deficient Patients

Investigators determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following hematopoietic stem cell transplantation. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. [JCI Insight] Abstract | Full Article

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Targeting CLL-1 for Acute Myeloid Leukemia Therapy

The authors review the expression of CLL-1 on normal cells and acute myeloid leukemia (AML), the value of CLL-1 in diagnosis and follow-up, and targeting CLL-1 therapy-based antibody and chimeric antigen receptor T cell therapy as well as providing an overview of CLL-1 as a target for AML. [J Hematol Oncol] Full Article

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

Intellia Therapeutics Presents New In Vivo and Engineered Cell Therapy Data

Intellia Therapeutics, Inc. will present new data, including the first demonstration of targeted gene insertion with CRISPR/Cas9 in the liver of non-human primates. Researchers also will present new in vitro data from Intellia’s lead engineered cell therapy program in acute myeloid leukemia. [Press release from Intellia Therapeutics, Inc. discussing research presented at the 22^nd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), Washington, DC] Press Release

miRagen Announces New Clinical Data for Cobomarsen in ATLL Patients

miRagen Therapeutics, Inc. announced incremental new data from its Phase I clinical trial evaluating the safety, tolerability and efficacy of cobomarsen, an inhibitor of microRNA-155, in adult T-cell leukemia/lymphoma (ATLL) in an oral presentation. [Press release from miRagen Therapeutics, Inc. discussing research presented at the 19^th International Congress HTLV 2019, Lima] Press Release

Orchard Therapeutics Announces Clinical Proof-of-Concept Data for Gene Therapy OTL-300 Demonstrating Efficacy in Transfusion-Dependent Beta-Thalassemia

Orchard Therapeutics announced the presentation of the full clinical proof-of-concept data from its trial of ex vivo, autologous, HSC gene therapy, OTL-300, for the treatment of transfusion-dependent beta-thalassemia. [Press release from Orchard Therapeutics plc discussing research presented at the 22^nd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), Washington, DC] Press Release

Forty Seven Inc. Expands Collaboration with Genentech to Include Third Clinical Trial in Non-Hodgkin’s Lymphoma

Forty Seven Inc. announced an extension of its agreement with Genentech, a member of the Roche Group. Under the terms of the extension, the companies will initiate a third clinical trial, evaluating Forty Seven’s CD47 antibody 5F9 in combination with Genentech’s anti-CD20 antibody rituximab and anti-PDL1 antibody, atezolizumab, in patients with diffuse large B-cell lymphoma, an aggressive form of non-Hodgkin’s lymphoma. [Forty Seven Inc.] Press Release

Multiple Myeloma Research Foundation (MMRF) Venture Philanthropy Fund Invests in NexImmune to Advance Novel Immunotherapy Candidate into Clinical Trials

NexImmune and the MMRF have entered into a partnership to advance a promising new therapy into clinical trials for multiple myeloma patients. The MMRF’s newly formed Myeloma Investment Fund aims to attract the most promising companies and technologies to the field to advance new therapies for myeloma patients. [Multiple Myeloma Research Foundation] Press Release

I-Mab Biopharma and MorphoSys Announce First Patient Dosed in Phase III Clinical Study of TJ202/MOR202 in Multiple Myeloma

I-Mab Biopharma and MorphoSys AG announced that the first patient has been dosed in a Phase III randomized and multi-center clinical study in Taiwan to evaluate MorphoSys’ investigational human CD38 antibody TJ202/MOR202 in combination with lenalidomide in patients with relapsed or refractory multiple myeloma. [I-Mab Biopharma Co., Ltd.] Press Release

G1 Therapeutics Announces Positive Feedback from Trilaciclib End-of-Phase II Meeting with FDA; Expects to File NDA in 2020

G1 Therapeutics, Inc. provided a regulatory update on trilaciclib, a first-in-class myelopreservation agent designed to protect the bone marrow from damage by chemotherapy and improve patient outcomes. [G1 Therapeutics, Inc.] Press Release

TC BioPharm Initiates Phase I Trial of Allogeneic Gamma Delta T Cell Therapy in Acute Myeloid Leukemia Patients

TC BioPharm announced it has initiated a Phase I clinical study of TCB002, an allogeneic cell therapy consisting of activated and expanded gamma delta T cells. The trial, for treatment of patients suffering from acute myeloid leukemia, is being conducted at the Institute of Hematology and Blood Transfusion in Prague, Czech Republic. [TC BioPharm Ltd.] Press Release

Orchard Therapeutics Announces First Patient Dosed with Cryopreserved Formulation of OTL-103 Gene Therapy for the Treatment of Wiskott-Aldrich Syndrome

Orchard Therapeutics announced that the first patient with Wiskott-Aldrich Syndrome has been dosed in a open label study designed to evaluate engraftment of the cryopreserved formulation of OTL-103, its ex vivo autologous hematopoietic stem cell gene therapy. [Orchard Therapeutics plc] Press Release

Xencor Announces Partial Clinical Hold Lifted on Phase I Study of XmAb^®14045

Xencor, Inc. announced the FDA has lifted the partial clinical hold that was placed on the Phase I study of XmAb14045, a CD123 x CD3 bispecific antibody molecule being evaluated in patients with relapsed or refractory acute myeloid leukemia and other CD123-expressing hematologic malignancies. [Xencor, Inc.] Press Release

Teneobio Announces US FDA Approval of the Investigational New Drug Application for TNB-383B and the Initiation of Phase I Clinical Studies in Multiple Myeloma Patients

Teneobio, Inc. and its affiliate TeneoOne, Inc. announced that their investigational new drug application for TNB-383B, a bispecific T-cell engaging antibody for the treatment of multiple myeloma, was cleared for the initiation of Phase I clinical studies by the FDA. The ongoing development of TNB-383B is being pursued in collaboration with AbbVie, Inc. [Teneobio, Inc.] Press Release

Celgene Corporation and Acceleron Pharma Announce Submission of Luspatercept Marketing Authorization Application to the European Medicines Agency (EMA) for MDS and Beta-Thalassemia

Celgene Corporation and Acceleron Pharma Inc. announced that Celgene has submitted a Marketing Authorization Application to the EMA for luspatercept for the treatment of adult patients with very low to intermediate-risk myelodysplastic syndromes-associated anemia who have ring sideroblasts, require red blood cell (RBC) transfusions and have received or are not eligible for erythropoiesis-stimulating agents, and for the treatment of adult patients with beta-thalassemia-associated anemia who require RBC transfusions. [Celgene Corporation] Press Release

US Biopharma Company Undertakes Anti-Cancer Clinical Trials in Poland, First Patient Showing Positive Initial Treatment

A small public company with six highly promising anti-cancer drugs in the pipeline is augmenting US clinical trials with trials in Poland, speeding the process of patient recruitment and data collection. The company, Moleculin, recently recruited three patients in six weeks in Poland, whereas in the US it took a full year to build a similar, complete cohort. The company now has two clinical trials with patients enrolled in Poland. [Moleculin] Press Release

House Panel Proposes $2 Billion Increase for NIH

A spending panel in the US House of Representatives has proposed giving the National Institutes of Health (NIH) a $2 billion raise, for a total of $41.1 billion, in a draft bill released. If adopted, that 5% raise for the 2020 fiscal year that begins on 1 October would more than reverse a $5 billion cut recommended by President Donald Trump, whose three budget blueprints have all called for slashing NIH funding. [ScienceInsider] Editorial

US Science Academy Leaders Approve Plan to Expel Sexual Harassers

The US National Academy of Sciences (NAS) is moving ahead with a policy that would allow it to expel members found guilty of sexual harassment. The academy’s governing council voted to proceed with the plan at the NAS annual meeting in Washington DC. [Nature News] Editorial

NEW International Conference on Cellular Therapies: Focus on Immune Based Therapeutic Concepts
September 20-22, 2019
Mandelieu, France

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NEW 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)

Postdoctoral Researcher – Stem Cells & Erythropoiesis in MDS (Karolinska Institutet)

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)

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