Hematopoiesis News Volume 10.12 | Apr 2 2019

TOP STORY

The Mitochondrial Transacylase, Tafazzin, Regulates for AML Stemness by Modulating Intracellular Levels of Phospholipids

Through a CRISPR screen, scientists identified tafazzin (TAZ) as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. [Cell Stem Cell] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

The Chromatin Binding Protein Phf6 Restricts the Self-Renewal of Hematopoietic Stem Cells

Mechanistically, Phf6 directly and indirectly activated downstream effectors in TNFα signaling. The Phf6 deletion repressed the expression of a set of genes associated with TNFα signaling, thereby conferring resistance against the TNFα-mediated growth inhibition on HSCs. [Blood] Abstract

Impaired Human Hematopoiesis Due to a Cryptic Intronic GATA1 Splicing Mutation

Investigators characterized two unrelated patients with a distinct presentation of dyserythropoietic anemia and other impairments in hematopoiesis associated with an intronic mutation in GATA1 that is 24 nucleotides upstream of the canonical splice acceptor site. Functional studies demonstrated that this single-nucleotide alteration led to reduced canonical splicing and increased use of an alternative splice acceptor site that caused a partial intron retention event. [J Exp Med] Abstract

The Novel Dihydroorotate Dehydrogenase (DHODH) Inhibitor BAY 2402234 Triggers Differentiation and Is Effective in the Treatment of Myeloid Malignancies

Researchers describe the discovery and characterization of BAY 2402234 – a novel, potent, selective and orally bioavailable DHODH inhibitor that showed monotherapy efficacy and differentiation induction across multiple acute myeloid leukemia subtypes. [Leukemia] Full Article

Hematopoietic Niche Drives FLT3-ITD Acute Myeloid Leukemia Resistance to Quizartinib via STAT5- and Hypoxia- Dependent Up-Regulation of AXL

The authors demonstrated that convergent signals from hematopoietic microenvironment drove Fms-like tyrosine kinase 3 (FLT3-ITD) cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. [Haematologica] Abstract

The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells

Transcriptional analysis of purified leukemia-initiating stem cell populations revealed that deficiency of NOX2 collapsed the self-renewal program and activated inflammatory and myeloid-differentiation-associated programs. Downstream of NOX2, scientists identified the forkhead transcription factor FOXC1 as a mediator of the phenotype. Notably, suppression of NOX2 or FOXC1 led to marked differentiation of leukemic blasts. [Cell Rep] Full Article | Graphical Abstract

MicroRNA 34a Promotes Ionizing Radiation-Induced DNA Damage Repair in Murine Hematopoietic Stem Cells

Reduced numbers and DNA damage repair, as well as increased apoptosis, were observed in HSCs from miR-34a-deficient mice induced by irradiation, although miR-34a was dispensable for steady-state hematopoiesis. Further investigations showed that HSCs deficient in miR-34a exhibited decreased expressions of DNA repair-associated genes involved in homologous recombination and nonhomologous end joining. [FASEB J] Abstract

CLINICAL RESEARCH

Clinical, Histopathological and Molecular Characterization of Hypoplastic Myelodysplastic Syndrome

Investigators delineated clinical, histopathological, and molecular features of hypoplastic myelodysplasic syndrome (MDS), based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM, and 727 with normo- or hypercellular MDS. [Leukemia] Abstract

Phase I Trial of Isatuximab Monotherapy in the Treatment of Refractory Multiple Myeloma

Patients progressing on or after standard therapy received intravenous isatuximab. The primary objective was to determine the maximum tolerated dose (MTD) of isatuximab. Overall, 84 patients received ≥1 dose of isatuximab. The MTD was not reached; no cumulative adverse reactions were noted. [Blood Cancer J] Full Article

High IFITM3 Expression Predicts Adverse Prognosis in Acute Myeloid Leukemia

Multivariate analysis demonstrated that high interferon-induced transmembrane protein (IFITM) 3 expression was an independent risk factor for event-free survival (EFS) and overall survival (OS) in patients only received chemotherapy. In patients who underwent allogeneic hematopoietic stem cell transplantation, however, all IFITM members had no impact on either EFS or OS. [Cancer Gene Ther] Abstract

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The Role of ASXL1 in Hematopoiesis and Myeloid Malignancies

The authors summarize the clinical implications of additional sex combs-like 1 (ASXL1) mutations, the role of wild-type ASXL1 in normal hematopoiesis, and oncogenic functions of mutant ASXL1 in myeloid neoplasms. [Cell Mol Life Sci] Abstract

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

Orchard Therapeutics Presents New Registrational Data Demonstrating Sustained Clinical Benefit of OTL-200 for the Treatment of MLD

Orchard Therapeutics presented the full registrational dataset from a 20 patient trial evaluating the efficacy and safety of OTL-200, an ex vivo autologous HSC-based gene therapy for the treatment of metachromatic leukodystrophy (MLD). [Press release from Orchard Therapeutics discussing research presented at the 45^th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Frankfurt] Press Release

BioLineRx Announces Successful Engraftment Data from Phase III GENESIS Trial for BL-8040 in Multiple Myeloma Patients

BioLineRx Ltd. announced that HSCs mobilized by BL-8040 in combination with granulocyte colony-stimulating factor (G-CSF) were successfully engrafted in all 11 patients participating in the Part 1, lead-in period of the GENESIS trial, a double-blind, placebo-controlled Phase III trial comparing BL-8040 and G-CSF to G-CSF alone, in mobilization of HSCs for autologous transplantation in multiple myeloma patients. [Press release from BioLineRx Ltd. discussing research presented at the 45^th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Frankfurt] Press Release

Aptevo Therapeutics Presents New Preclinical Data for APVO436 and ALG.APV-527

Aptevo Therapeutics Inc. announced that new preclinical data for two ADAPTIR bispecific candidates, APVO436, a bispecific antibody candidate targeting CD123 and CD3, and ALG.APV-527, a bispecific antibody candidate targeting 4-1BB and 5T4, were presented. [Press release from Aptevo Therapeutics Inc. discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

Initial Results from Autolus Therapeutics’ ALLCAR19 Phase I/II Trial in Adult Acute Lymphoblastic Leukemia Presented

Autolus Therapeutics plc announced that Claire Roddie MB, PhD, FRCPath, presented initial data from the ongoing Phase I/II ALLCAR19 trial of AUTO1 in adult acute lymphoblastic B cell leukemia as a late-breaking poster presentation. [Press release from Autolus Therapeutics plc discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

G Therapeutics Reports Positive Interim Data from UNITY-NHL Phase IIb Trial Evaluating Umbralisib Monotherapy in Patients with Marginal Zone Lymphoma

G Therapeutics, Inc. reported positive interim data from the ongoing single-arm marginal zone lymphoma cohort of its Phase IIb clinical trial known as UNITY-NHL. [Press release from G Therapeutics, Inc. discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

Aptose Presents New Preclinical Data on CG-806 and APTO-253

Aptose Biosciences Inc. announced that new preclinical data for CG-806, its first-in-class, highly potent oral small molecule pan-FLT3/pan-BTK inhibitor, and APTO-253, its MYC inhibitor, were being presented in two separate posters. [Press release from Aptose Biosciences Inc. discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

Phase III ADMIRAL Trial Data Show XOSPATA^® (Gilteritinib) Significantly Prolongs Overall Survival in Adult Patients with FLT3 Mutation-Positive Relapsed/Refractory Acute Myeloid Leukemia

Astellas Pharma Inc. announced results from the Phase III ADMIRAL clinical trial comparing XOSPATA^® to salvage chemotherapy in adult patients with relapsed or refractory Acute Myeloid Leukemia with a FLT3 mutation. [Press release from Astellas Pharma Inc. discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

Kura Oncology Identifies Farnesylated Proteins Associated with CXCL12 Expression, Potential Biomarker of Clinical Benefit from Tipifarnib in Lymphoma Indications

Kura Oncology, Inc. reported new findings regarding the mechanism of action of the company’s lead drug candidate tipifarnib and its potential clinical applications. [Press release from Kura Oncology, Inc. discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

AVEO and Biodesix Announce Positive Results from Phase Ib Ficlatuzumab-Cytarabine Trial in Patients with Relapsed and Refractory AML

AVEO Oncology and Biodesix, Inc. announced results from an investigator-sponsored Phase Ib expansion cohort of ficlatuzumab, AVEO’s potent hepatocyte growth factor inhibitory antibody product candidate, in combination with cytarabine in patients with relapsed and refractory acute myeloid leukemia (AML). [Press release from AVEO Oncology discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

Phase Ib/II Dose Escalation Trial of Onvansertib in Relapsed/Refractory AML Demonstrates Safety, Tolerability and Relative Durability with Complete Responses at Highest Dose Levels

Trovagene, Inc. presented new data from its ongoing Phase Ib/II study evaluating onvansertib in combination with standard-of-care chemotherapy in Acute Myeloid Leukemia (AML). [Press release from Trovagene, Inc. discussing research presented at the American Association for Cancer Research (AACR) 2019 Annual Meeting, Atlanta] Press Release

Achillion Announces Completion of Enrollment in Phase II PNH Combination Trial

Achillion Pharmaceuticals, Inc. announced achievement of enrollment in their ACH-4471 Phase II paroxysmal nocturnal hemoglobinuria (PNH) trial in combination with eculizumab. [Achillion Pharmaceuticals, Inc.] Press Release

Cellect Announces Positive Phase I/II Mid-Study Results of Its ApoGraft™ Technology

Cellect Biotechnology Ltd. announced positive mid-study data from the company’s Phase I/II study of its ApoGraft™ technology. The first half of patients planned for the study have completed the 180 day follow up, and 8 out of 12 planned subjects have been enrolled. [Cellect Biotechnology Ltd. (PR Newswire Association LLC.)] Press Release

Triphase Accelerator Initiates Phase I Clinical Trial of TRPH-222 in B-Cell Lymphoma

Triphase Accelerator Corporation announced that Triphase Accelerator’s TRPH-222, an anti-CD22 antibody-drug conjugate for the treatment of patients with lymphoma, has been dosed in the first patient in a Phase I clinical trial. [Triphase Accelerator Corporation (GlobeNewswire, Inc.)] Press Release

Celgene Receives CHMP Positive Opinions for Both REVLIMID^® (Lenalidomide) and IMNOVID^® (Pomalidomide)-Based Triplet Combination Regimens for Patients with Multiple Myeloma

Celgene Corporation announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted positive opinions for two triplet regimens based on Celgene’s proprietary IMiD^® medications, REVLIMID and IMNOVID. [Celgene Corporation] Press Release

Bluebird Bio Receives Positive Opinion from CHMP for ZYNTEGLO™ (Autologous CD34⁺ Cells Encoding βA-T87Q-Globin Gene) Gene Therapy for Patients 12 Years and Older with Transfusion-Dependent β-Thalassemia (TDT) Who Do Not Have β0/β0 Genotype

bluebird bio, Inc. announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion recommending conditional marketing authorization for ZYNTEGLO™, a gene therapy for patients 12 years and older with TDT who do not have a β0/β0 genotype, for whom HSC transplantation is appropriate but a human leukocyte antigen-matched related HSC donor is not available. [bluebird bio, Inc.] Press Release

Imbrium Therapeutics Announces US FDA Orphan Drug Designation for Tinostamustine for the Treatment of T-Cell Prolymphocytic Leukemia

Imbrium Therapeutics L.P. in conjunction with Mundipharma EDO GmbH, announced that the FDA has granted orphan drug designationto its investigational drug tinostamustine, a potentially first-in-class alkylating deacetylase inhibiting molecule being studied in early phase clinical trials, for the treatment of T-cell prolymphocytic leukemia. [Imbrium Therapeutics L.P.] Press Release

Agios Receives FDA Breakthrough Therapy Designation for TIBSOVO^® (Ivosidenib) in Combination with Azacitidine for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) with an IDH1 Mutation in Adult Patients Ineligible for Intensive Chemotherapy

Agios Pharmaceuticals, Inc. announced that the FDA has granted Breakthrough Therapy designation for TIBSOVO^® in combination with azacitidine for the treatment of newly diagnosed AML with an IDH1 mutation in adult patients who are ≥75 years old or who have comorbidities that preclude use of intensive induction chemotherapy. [Agios Pharmaceuticals, Inc.] Press Release

First Gene Therapy to Treat Rare Blood Disease Nears European Approval

Lentiglobin, the gene therapy for beta-thalassemia developed by Cambridge, Mass.-based Bluebird Bio, was recommended for approval by the Committee for Medicinal Products for Human Use, the drug-reviewing arm of the European Medicines Agency. A final approval decision is expected within the next three months. [STAT News] Editorial

What Thailand’s Long-Awaited Election Could Mean for Science

Thailand is bracing for the results of its first election since a military junta took charge in a 2014 coup. Scientists, like many other people in Thailand, want a more democratic country. But whether a pro-democracy party or a military-backed one ends up in charge, science is likely to prosper as a result of ongoing reforms put in place by the junta that are likely to continue under either government. [Nature News] Editorial

NEW Gordon Research Conference: Red Cells: Erythropoiesis & the Erythrocyte
July 14-19, 2019
Newport, Rhode Island, United States

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

NEW 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)

Postdoctoral Scholarship – Murine Erythropoiesis (Lund University)

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)

Postdoctoral Position – RNA Modifications, Hematopoiesis & Cancer (Lund University)

Postdoctoral Research Fellow – Development of Lymphoid Cells (Lund University)

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

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