Hematopoiesis News Volume 10.15 | Apr 23 2019

TOP STORY

U2AF1 Mutations Induce Oncogenic IRAK4 Isoforms and Activate Innate Immune Pathways in Myeloid Malignancies

Expression of interleukin-1 receptor-associated kinase 4 (IRAK4)-long (L) was mediated by mutant U2 small nuclear RNA auxiliary factor 1 (U2AF1) and was associated with oncogenic signaling in myelodysplastic syndromes and acute myeloid leukemia (AML). Inhibition of IRAK4-L abrogated leukemic growth, particularly in AML cells with higher expression of the IRAK4-L isoform. [Nat Cell Biol] Abstract | Press Release

(Ranked by impact factor of the journal)

Vitamin K-Antagonism Impairs the Bone Marrow Microenvironment and Hematopoiesis

Researchers showed that vitamin K antagonists (VKA) altered parameters of bone physiology and reduced functional HSC eight fold. They implicated impairment of the functional, secreted, vitamin K-dependent, γ-carboxylated form of periostin by macrophages and – to a lesser extent – mesenchymal stem cells of the bone marrow microenvironment and integrin β3-AKT signaling in HSC as at least partly causative of this effect, with VKA not being directly toxic to HSC. [Blood] Abstract

Ttc7a Regulates Haematopoietic Stem Cell Functions While Controlling the Stress-Induced Response

Tetratricopeptide repeat domain 7 A (Ttc7a)-deficient HSCs exhibited a different transcriptomic profile for a set of genes controlling the cellular response to stress, which was associated with increased proliferation in response to chemically induced stress in vitro and myeloablative stress in vivo. [Haematologica] Full Article

Non-Genotoxic MDM2 Inhibition Selectively Induces Pro-Apoptotic P53 Gene Signature in Chronic Lymphocytic Leukemia Cells

Investigators tested the second-generation mouse double-minute-2 homolog (MDM2) inhibitor, RG7388, in patient-derived chronic lymphocytic leukemia cells and normal cells, examining its effect on the induction of p53-transcriptional targets. RG7388 potently decreased viability in p53-functional chronic lymphocytic leukemia cells whereas p53-non-functional samples were more drug-resistant. [Haematologica] Full Article

Phenformin, but Not Metformin, Delays Development of T Cell Acute Lymphoblastic Leukemia/Lymphoma via Cell-Autonomous AMPK Activation

Scientists report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Phenformin enhanced apoptosis in T-ALL cells both in vivo and in vitro. [Cell Rep] Full Article | Press Release | Graphical Abstract

LncRNA Spehd Regulates Hematopoietic Stem and Progenitor Cells and Is Required for Multilineage Differentiation

To understand the roles that long non-coding RNAs (lncRNAs) may play in hematopoiesis, researchers selected a subset of mouse lncRNAs with potentially relevant expression patterns and refined the candidate list using evidence of conserved expression in human blood lineages. [Cell Rep] Full Article | Graphical Abstract

BRD9 Binds Cell Type-Specific Chromatin Regions Regulating Leukemic Cell Survival via STAT5 Inhibition

The authors showed that bromodomain-containing protein 9 (BRD9) was overexpressed in acute myeloid leukemia (AML) cells including ex vivo primary blasts compared with CD34⁺ cells. By targeting BRD9 expression in AML, they observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. [Cell Death Dis] Full Article

Iron Deficiency Disrupts Embryonic Hematopoiesis but Not the Endothelial to Hematopoietic Transition

Investigators found that iron deficiency did not block the endothelial to hematopoietic transition, the first step of hematopoiesis. However, it did reduce the proliferation, survival and clonogenic capacity of hematopoietic progenitors. Surprisingly, iron deficiency affected erythro-myeloid progenitors significantly more than the primitive erythroid ones. [Sci Rep] Full Article

Interleukin-33 Regulates Hematopoietic Stem Cell Regeneration after Radiation Injury

Mice with IL-33 receptor deficiency showed decreased HSC regeneration and mouse survival after total body irradiation. Of note, IL-33 reduced radiation-induced apoptosis of HSCs and mediated this effect through repression of the p53-PUMA pathway. [Stem Cell Res Ther] Full Article

CLINICAL RESEARCH

Clinical, Immunophenotypic, and Genomic Findings of Acute Undifferentiated Leukemia and Comparison to Acute Myeloid Leukemia with Minimal Differentiation: A Study from the Bone Marrow Pathology Group

Compared to acute myeloid leukemia with minimal differentiation, acute undifferentiated leukemia cases were characterized by more frequent mutations in PHF6 and more frequent expression of TdT on blasts while acute myeloid leukemia with minimal differentiation cases had more frequent CD123 expression. [Mod Pathol] Abstract

Serum GM3(d18:1–16:0) and GM3(d18:1–24:1) Levels May Be Associated with Lymphoma: An Exploratory Study with Hematological Diseases

In all the subjects with hematological diseases, monosialodihexosylganglioside (GM3)(d18:1-16:0) were inversely correlated with erythrocyte counts. Regarding the difference in serum GM3 molecular species levels among each hematological diseases and healthy subjects, the levels of GM3(d18:1-16:0) and GM3(d18:1-24:1) were higher in the lymphoid neoplasm group than healthy subjects. [Sci Rep] Full Article

Subscribe to one of our other 19 science newsletters such as Cord Blood News & Cell Therapy News.

MicroRNAs as Regulators and Effectors of Hematopoietic Transcription Factors

MiRs function as downstream effectors of hematopoietic transcription factors and as upstream regulators to control transcription factor levels. Multiple miRs have been shown to play essential roles. The authors focus on hematopoietic miRs that function as upstream regulators of central hematopoietic transcription factors required for normal hematopoiesis. [Wiley Interdiscip Rev RNA] Abstract | Graphical Abstract

Cytokine-Induced Hematopoietic Stem and Progenitor Cell Mobilization: Unraveling Interactions between Stem Cells and Their Niche

Investigators provide an overview of the events that underlie hematopoietic stem and progenitor cell mobilization and address the relevant cellular and molecular components of the bone marrow niche. Furthermore, current and future mobilizing agents will be discussed. [Ann N Y Acad Sci] Full Article

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

BerGenBio to Present NSCLC and AML Clinical Data from Phase II Development Programme with Selective AXL Inhibitor Bemcentinib

BerGenBio ASA announced that the company and its collaborators will present new interim clinical and biomarker data from its extensive Phase II clinical development program with bemcentinib, a selective, oral AXL inhibitor. [Press release from BerGenBio ASA discussing research presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO), Chicago] Press Release

GlycoMimetics Announces Enrollment of First Patient in NCI-Sponsored Phase III Trial of Uproleselan in AML

GlycoMimetics, Inc. announced dosing of the first patient in a Phase III clinical trial being conducted under the auspices of a Cooperative Research and Development Agreement between GlycoMimetics and the National Cancer Institute, part of the National Institutes of Health. [GlycoMimetics, Inc.] Press Release

Precision BioSciences Announces Dosing of First Patient in Off-the-Shelf CAR T Cell Therapy Phase I/IIa Clinical Trial

Precision BioSciences announced it has dosed the first patient in the Phase I/IIa clinical trial of PBCAR0191, its first gene-edited allogeneic anti-CD19 chimeric antigen receptor (CAR) T cell product candidate. This CAR T cell product candidate is being evaluated in adult patients with relapsed or refractory (R/R) non-Hodgkin lymphoma or R/R B-cell precursor acute lymphoblastic leukemia as an off-the-shelf cell therapy. [Precision BioSciences] Press Release

Rovagene Announces Data Demonstrating Significant Synergy of Onvansertib in Combination with Venetoclax in Cell Model of Venetoclax-Resistant AML

Trovagene, Inc. announced preclinical data that evaluated the effect of combining onvansertib with venetoclax in an AML cell model known to be resistant to venetoclax. This combination demonstrated synergy with a significant decrease in tumor cell viability. [Trovagene, Inc.] Press Release

Affimed Provides Regulatory Update on AFM11 Clinical Program

Affimed N.V. announced that it has submitted to the FDA additional information to Affimed’s initial response document submitted in early March relating to the previously-announced clinical hold on AFM11. The additional information addresses the request from the FDA for the clinical trial protocol for the study of AFM11 for treatment of acute lymphocytic leukemia. [Affimed N.V.] Press Release

Autolus Therapeutics Receives FDA Orphan Drug Designation for AUTO3 for Treatment of Acute Lymphoblastic Leukemia

Autolus Therapeutics plc announced that the FDA has granted orphan drug designation to autologous enriched T-cells genetically modified with a retroviral vector to express two chimeric antigen receptors targeting CD19 and CD22 (AUTO3) for the treatment of acute lymphoblastic leukemia. [Autolus Therapeutics plc] Press Release

ExCellThera’s Lead Technology, ECT-001, Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation

ExCellThera Inc. announced that the FDA has granted RMAT designation to its lead technology, ECT-001, in the treatment of hematologic malignancies. The RMAT designation is based on strong data from Phase I/II clinical trials using ECT-001 to expand stem and immune cells for the treatment of blood cancers. [ExCellThera Inc.] Press Release

Moleculin Receives FDA Approval of Fast Track Designation for Annamycin

Moleculin Biotech, Inc. announced that the FDA has approved its request for Fast Track Designation for its drug, Annamycin, for the treatment of relapsed or refractory acute myeloid leukemia. [Moleculin Biotech, Inc.] Press Release

Gracell Bio Announces FasT CAR-T, a Breakthrough Technology for Hematological Malignancies

Gracell Biotechnologies, Co., Ltd. announced it has developed FasT CAR-T, a revolutionary platform that shortens the manufacturing time of CAR-T treatments from two weeks to one day. FasT CAR-T also lowers manufacturing costs to a fraction of previous CAR-T therapies, while showing higher potency of CD19-directed FasT CAR-T in B-Cell acute lymphoblastic leukemia and non-Hodgkin Lymphoma, both in vitro and in vivo. [Gracell Biotechnologies, Co., Ltd. (PR Newswire Association LLC.)] Press Release

Versiti Blood Research Institute Awarded Multi-Million Dollar REDS-IV Blood Study Contract

Versiti Blood Research Institute has been awarded a 7-year federal contract valued at $7.4 million from the US Department of Health & Human Services to participate in the National Heart, Lung, and Blood Institute’s research program to protect the nation’s blood supply and improve the collection and use of blood products. [Versiti Blood Research Institute] Press Release

Three Researchers Ousted from MD Anderson

MD Anderson Cancer Center has ousted three researchers for violating granting agency policies, reports the Houston Chronicle. Last year, the National Institutes of Health notified the center of five grantees there who were under investigation, reports the Chronicle. [The Scientist] Editorial

After Firings, MD Anderson Officials Try to Calm Fears of Racial Profiling

Administrators at the MD Anderson Cancer Center in Houston, Texas, tried to reassure alarmed employees that its recent dismissals of faculty members alleged to have broken federal funding rules were not connected to race or ethnicity. [ScienceInsider] Editorial

NEW Keystone Symposia: Hematopoiesis
April 3-7, 2020
Big Sky, Montana, United States

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

NEW Assistant Professor – Lymphoma/Myeloma Research (The University of Texas MD Anderson Cancer Center)

NEW 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)

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

Recruit Top Talent: Reach potential candidates by posting your organization’s career opportunities on the Connexon Creative Job Board at no cost.

Have we missed an important article or publication in Hematopoiesis News? Click here to submit!

Comments or suggestions? Submit your feedback here.