Hematopoiesis News Volume 10.24 | Jun 25 2019

TOP STORY

TNF-α Coordinates Hematopoietic Stem Cell Survival and Myeloid Regeneration

Researchers showed that while inducing myeloid progenitor apoptosis, tumor necrosis factor α (TNF-α) promoted HSC survival and myeloid differentiation by activating a strong and specific p65-nuclear factor κB-dependent gene program that primarily prevented necroptosis rather than apoptosis, induced immunomodulatory functions, and poised HSCs for myeloid cell production. [Cell Stem Cell] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

Targetable Genetic Alterations of TCF4 (E2-2) Drive Immunoglobulin Expression in Diffuse Large B Cell Lymphoma

The TCF4 gene was one of the top BRD4-regulated genes in diffuse large B cell lymphoma (DLBCL) cell lines. BET proteolysis-targeting chimera ARV771 extinguished TCF4, MYC, and immunoglobulin μ expression and killed activated B cell-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. [Sci Transl Med] Abstract

PRMT1-Mediated FLT3 Arginine Methylation Promotes Maintenance of FLT3-ITD⁺ Acute Myeloid Leukemia

Investigators showed that expression of PRMT1, the primary type I arginine methyltransferase, significantly increased in acute myeloid leukemia (AML) cells relative to normal hematopoietic cells. They indicated that PRMT1 preferentially cooperated with FLT3-ITD contributing to AML maintenance. Genetic or pharmacological inhibition of PRMT1 markedly blocked FLT3-ITD⁺ AML cell maintenance. [Blood] Abstract

Targeting Enhancer Switching Overcomes Non-Genetic Drug Resistance in Acute Myeloid Leukemia

Using single cell RNA-sequencing of paired drug naïve and resistant acute myeloid leukemia patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, the authors demonstrated that transcriptional plasticity drove stable epigenetic resistance. With a CRISPR-Cas9 screen they identified regulators of enhancer function as important modulators of the resistant cell state. [Nat Commun] Full Article

Small-Molecule Targeting of MUSASHI RNA-Binding Activity in Acute Myeloid Leukemia

Scientists found that the small molecule Ro 08-2750 (Ro) bound directly and selectively to MUSASHI (MSI) RNA binding protein 2 (MSI2) and competed for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells resulted in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. [Nat Commun] Full Article

Activation of JAK/STAT Signaling in Megakaryocytes Sustains Myeloproliferation In Vivo

JAK2^V617F-mutant presence in megakaryocytes was sufficient to induce enhanced erythropoiesis and promote fibrosis, which led to a myeloproliferative state with expansion of mutant and non-mutant hematopoietic cells. The increased erythropoiesis was associated with elevated interleukin-6 level, which was also required for aberrant erythropoiesis in vivo. [Clin Cancer Res] Abstract

Enhancement of LIN28B-Induced Hematopoietic Reprogramming by IGF2BP3

Using proteomics and in situ analyses, researchers found that Lin28b directly interacted with Igf2bp3, another RNA-binding protein, and their enforced co-expression in adult hematopoietic stem and progenitor cells reactivated fetal-like B-cell development in vivo more efficiently than either factor alone. [Genes Dev] Abstract

Control of Hematopoietic Stem and Progenitor Cell Function through Epigenetic Regulation of Energy Metabolism and Genome Integrity

DPY30 directly regulated expression of several key glycolytic genes, and its loss in hematopoietic stem and progenitor cells (HSPCs) critically impaired energy metabolism, including both glycolytic and mitochondrial pathways. The authors also found significant increase in DNA breaks as a result of impaired DNA repair upon DPY30 loss, and inhibition of DNA damage response partially rescued clonogenicity of the DPY30-deficient HSPCs. [Stem Cell Reports] Full Article | Graphical Abstract

Hemogenic Endothelial Cells Can Transition to Hematopoietic Stem Cells through a B-1 Lymphocyte-Biased State during Maturation in the Mouse Embryo

Investigators employed direct transplantation assays of CD45^–VE-cadherin(VC)⁺KIT⁺(V⁺K⁺) cells into immunodeficient neonatal mice that permitted engraftment of embryonic hematopoietic precursors. They found that freshly isolated V⁺K⁺ cells exhibited significantly greater B-1 lymphocyte-biased repopulating capacity than multilineage repopulating capacity. [Stem Cell Reports] Full Article | Graphical Abstract

CLINICAL RESEARCH

T Cell Receptor Gene Therapy Targeting WT1 Prevents Acute Myeloid Leukemia Relapse Post-Transplant

Scientists isolated a high-affinity Wilms’ tumor antigen 1-specific T cell expressing receptor (TCR) 4 (TCR_C4) from HLA-A2⁺ normal donor repertoires, inserted TCR_C4 into Epstein-Bar virus-specific donor CD8⁺ T cells to minimize graft-versus-host disease risk and enhance transferred T cell survival and infused these cells prophylactically post-hematopoietic cell transplantation into 12 patients. [Nat Med] Abstract | Press Release

Daratumumab-Based Regimens Are Highly Effective and Well Tolerated in Relapsed or Refractory Multiple Myeloma Regardless of Patient Age: Subgroup Analysis of the Phase III CASTOR and POLLUX Studies

The Phase III POLLUX and CASTOR studies demonstrated superior benefit of daratumumab plus lenalidomide/dexamethasone or bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Efficacy and safety of daratumumab was analyzed according to age groups of 65 to 74 years and ≥75 years. [Haematologica] Abstract

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Biological Characteristics and Regulation of Early Megakaryocytopoiesis

In this review, the authors focus on recent findings about differentiation from commitment of HSCs to megakaryocyte and its regulation, and discuss future directions in this research field. [Stem Cell Rev] Abstract

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

ADC Therapeutics Presents Clinical Data on ADCT-402 and ADCT-301 in Subtypes of Relapsed or Refractory Lymphoma

ADC Therapeutics presented data from subgroup analyses of its 183-patient Phase I clinical trial of ADCT-402 and 128-patient Phase I trial of ADCT-301, as well as preclinical data demonstrating the potential of both product candidates in combination with other therapies. [Press release from ADC Therapeutics discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

Verastem Oncology Presents COPIKTRA™ (Duvelisib) Data in Peripheral T-Cell Lymphoma

Verastem, Inc. announced an oral presentation highlighting supportive Phase I clinical data for duvelisib in patients with relapsed or refractory peripheral T-cell lymphoma. [Press release from Verastem, Inc. discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

Epizyme Reports Updated Data from Phase II Trial of Tazemetostat in Patients with Relapsed or Refractory Follicular Lymphoma

Epizyme, Inc. reported positive interim data from an ongoing Phase II trial of its lead candidate, tazemetostat, as a monotherapy for patients with relapsed or refractory follicular lymphoma who have received at least two prior lines of systemic therapy. [Press release from Epizyme, Inc. discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

TG Therapeutics Announces Data Presentations

TG Therapeutics, Inc. announced data from four presentations, including three oral presentations and one poster presentation. One presentation includes data from patients with chronic lymphocytic leukemia who are intolerant to prior BTK or PI3K delta inhibitor therapy who were then treated with single agent umbralisib. [Press release from TG Therapeutics, Inc. discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

Affimed Announces Clinical Data Update on Lead Product Candidate AFM13 in CD30⁺ Lymphoma

Affimed N.V. announced the presentation of data updates on two clinical studies. The data from an oral and a poster presentation featured Affimed’s lead innate cell engager AFM13, a first-in-class tetravalent, bispecific antibody derived from the ROCK^® platform that is being developed to treat CD30-positive lymphomas. [Press release from Affimed N.V. discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

Karyopharm Reports Updated Data from the Phase IIb SADAL Study

Karyopharm Therapeutics Inc. reported updated results from the Phase IIb SADAL study evaluating selinexor, the company’s first-in-class, oral selective inhibitor of nuclear export compound, in patients with relapsed or refractory diffuse large B-cell lymphoma after at least two prior multi-agent therapies and who are ineligible for transplantation, including high dose chemotherapy with stem cell rescue and CAR-T therapy. [Press release from Karyopharm Therapeutics Inc. discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

MEI Pharma Presents Updated Clinical Data from the ME-401 Phase Ib Study in Patients with Indolent B-Cell Malignancies

MEI Pharma, Inc. announced that updated data presented from a Phase Ib study of investigational ME-401, a selective oral inhibitor of PI3K delta, demonstrate an 83% overall response rate in patients with relapsed or refractory (r/r) follicular lymphoma and r/r chronic lymphocytic leukemia or small lymphocytic lymphoma. [Press release from MEI Pharma, Inc. discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

BeiGene Presents Pivotal Phase II Clinical Results of Zanubrutinib in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

BeiGene, Ltd. announced results from an ongoing pivotal Phase II clinical study of its investigational BTK inhibitor zanubrutinib being conducted in China in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma in an oral presentation. [Press release from BeiGene, Ltd. discussing research presented at the 15^th International Conference on Malignant Lymphoma (ICML), Lugano] Press Release

Gracell Data on Multi-Center Investigation of FasT CAR-19 Therapy Shows Positive First Impact in Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Gracell Biotechnologies Co., Ltd. announced preliminary results of a multi-center pilot study designed for evaluating the safety and efficacy of Gracell’s patented FasT CAR-19 investigational cell gene therapy. [Press release from Gracell Biotechnologies Co., Ltd. (PR Newswire Association LLC.) discussing research presented at the 2019 CAR-TCR Summit Asia, Shanghai] Press Release

ONO Enters into Exclusive License Agreement with Rafael Pharmaceuticals on CPI-613 (Devimistat), a Cancer Metabolism Inhibitor, and Other Related Compounds

Ono Pharmaceutical Co., Ltd. announced that it entered into an exclusive license agreement with Rafael Pharmaceuticals, Inc. for the development and commercialization of CPI-613, its first-in-class clinical lead compound, which targets cancer metabolism enzymes, as well as its other related compounds. [Ono Pharmaceutical Co., Ltd.] Press Release

AbbVie Announces US FDA Lifts Partial Clinical Hold on Phase III Study of Venetoclax in Patients with Multiple Myeloma Positive for the t(11;14) Genetic Abnormality

AbbVie announced that the FDA has lifted the partial clinical hold placed on CANOVA, a Phase III trial evaluating venetoclax for the investigational treatment of relapsed/refractory multiple myeloma. The CANOVA trial evaluates venetoclax in combination with dexamethasone versus pomalidomide in combination with dexamethasone in patients with relapsed/refractory multiple myeloma positive for the translocation (11;14) abnormality. [AbbVie Inc.] Press Release

Daiichi Sankyo Provides Update on FDA Review of Quizartinib for the Treatment of Patients with Relapsed/Refractory FLT3-ITD AML

Daiichi Sankyo Company, Limited announced that the company received a Complete Response Letter from the FDA for the New Drug Application of quizartinib for the treatment of adults with relapsed/ refractory FLT3-ITD acute myeloid leukemia (AML). [Daiichi Sankyo Company, Limited] Press Release

Japan’s MHLW Approves Invivoscribe’s LeukoStrat CDx FLT3 Mutation Assay as the CDx for Daiichi Sankyo’s Quizartinib for Treatment of Relapsed/Refractory FLT3-ITD AML. Expands Use to Include Specimens Collected in EDTA

Invivoscribe announced that the Ministry of Health, Labor and Welfare (MHLW) approved LeukoStrat^® CDx FLT3 Mutation Assay as the companion diagnostic for Daiichi Sankyo’s Quizartinib for the treatment of FLT3-ITD positive relapse/ refractory acute myeloid leukemia (AML) patients in Japan. [Invivoscribe, Inc] Press Release

Patent Office Reopens Major CRISPR Battle Between Broad Institute and Univ. of California

The US patent office has declared an interference between a dozen key patents awarded to the Broad Institute on the genome-editing technology CRISPR and ten CRISPR patent applications submitted by the University of California and its partners, according to documents posted by the US Patent and Trademark Office. [STAT News] Editorial

Iranian Biologists Face US Trial for Trying to Take Proteins Out of the Country

Three Iranian biologists are facing trial in a US court over charges that they violated trade sanctions by attempting to export chemicals known as growth factors, which are commonly used in medical research. The scientists have asked a federal district court judge in Atlanta, Georgia, to dismiss the criminal charges against them. [Nature News] Editorial

NEW The 5^th Canadian Cancer Research Conference
November 3-5, 2019
Ottawa, Ontario, Canada

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

NEW Senior Scientist – Immuno-Oncology of Hematologic Malignancies (University of Kansas School of Medicine)

NEW Postdoctoral Position – Hematopoietic Stem Cell Biology (Columbia University Irving Medical Center)

NEW Postdoctoral Position – Leukemia Research (University of California, San Francisco)

Postdoctoral Fellow – Hematopoietic Stem Cell Niche in Leukemia (Erasmus Medical Center)

Research Lab Specialist – Tumor Microenvironment & Cell Behavior (University of Southern California)

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

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

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

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

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

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