Hematopoiesis News Volume 10.25 | Jul 2 2019

TOP STORY

Synthetic Modeling Reveals HOXB Genes Are Critical for the Initiation and Maintenance of Human Leukemia

Investigators report an efficient, reproducible model of T-cell leukemia in which lentiviral transduction of normal human cord blood yielded aggressive leukemia that appeared indistinguishable from natural disease. They utilized this synthetic model to uncover a role for oncogene-induced HOXB activation which was operative in leukemia cells-of-origin and persisted in established tumors where it defined a novel subset of patients distinct from other known genetic subtypes and with poor clinical outcome. [Nat Commun] Full Article

(Ranked by impact factor of the journal)

Mutant H3 Histones Drive Human Pre-Leukemic Hematopoietic Stem Cell Expansion and Promote Leukemic Aggressiveness

Scientists examined 16 histone H3 genes in 434 primary acute myeloid leukemia (AML) samples and identified Q69H, A26P, R2Q, R8H and K27M/I mutations with higher incidence in secondary AML. These mutations occurred in pre-leukemic HSCs and existed in the major leukemic clones in patients. They increased the frequency of functional HSCs, altered differentiation, and amplified leukemic aggressiveness. [Nat Commun] Full Article

CRISPR/Cas9 Mediated ELANE Knockout Enables Neutrophilic Maturation of Primary Hematopoietic Stem and Progenitor Cells and Induced Pluripotent Stem Cells of Severe Congenital Neutropenia Patients

Researchers observed that granulocytic differentiation of ELANE knockout induced pluripotent stem cells and primary hematopoietic stem and progenitor cells were comparable to healthy individuals. Phagocytic functions, ROS production, and chemotaxis of the ELANE KO neutrophils were also normal. Knockdown of ELANE in the mutant ELANE expressing HL60 cells also allowed full maturation and formation of abundant neutrophils. [Haematologica] Abstract

Megakaryocyte Volume Modulates Bone Marrow Niche Properties and Cell Migration Dynamics

The authors found that megakaryocytes influenced migration of neutrophils and HSCs, and thus acted as biomechanical restrainers modulating cell mobility and extravasation. As a consequence of increased megakaryocyte volumes in platelet-depleted mice neutrophil mobility was reduced in these animals. [Haematologica] Abstract

Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo

Investigators were able to maintain engraftable quiescent HSCs for one month in culture under very low cytokine concentrations, hypoxia, and very high fatty acid levels. Exogenous fatty acids were required likely due to suppression of intrinsic fatty acid synthesis by hypoxia and low cytokine conditions. [Cell Rep] Full Article | Graphical Abstract

Bmi1 Suppresses Adipogenesis in the Hematopoietic Stem Cell Niche

Bmi1 was highly expressed in bone marrow stromal cells (BMSCs) but became downregulated upon adipogenic differentiation and during aging. Deleting Bmi1 from BMSCs increased marrow adipocytes, induced HSC quiescence and depletion, and impaired hematopoiesis. [Stem Cell Reports] Full Article | Graphical Abstract

CD166 Engagement Augments Mouse and Human Hematopoietic Progenitor Function via Activation of Stemness and Cell Cycle Pathways

Scientists demonstrated that CD166-CD166 homophilic interactions enhanced generation of murine and human hematopoietic progenitor cells in vitro and augmented hematopoietic function of these cells. [Stem Cells] Abstract

Retinoic Acid and Arsenic Trioxide Induce Lasting Differentiation and Demethylation of Target Genes in APL Cells

Researchers compared the effects of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) on NB4 and ATRA-resistant NB4-MR2 acute promyelocytic leukemia (APL) cells during treatment versus post treatment termination. After treatment termination, NB4 cells treated with ATRA or ATO reverted to non-differentiated cells, while combination-treated cells remained terminally differentiated. This effect was diminished in NB4-MR2 cells. [Sci Rep] Full Article

CLINICAL RESEARCH

Multicenter Analysis of Outcomes in Blastic Plasmacytoid Dendritic Cell Neoplasm Offers a Pre-Targeted Therapy Benchmark

Investigators defined the clinical characteristics and outcomes of a group of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) treated at three US cancer centers in the modern era but before tagraxofusp was available. In 59 studied patients with BPDCN, the median overall survival from diagnosis was 24 months and outcomes were similar in patients with “skin only” or with systemic disease at presentation. [Blood] Abstract

Elevated Lactate Dehydrogenase Has Prognostic Relevance in Treatment-Naïve Patients Affected by Chronic Lymphocytic Leukemia with Trisomy 12

Scientists performed an analysis of the association between demographic; clinical; laboratory; biologic features and outcome in chronic lymphocytic leukemia patients with +12 to identify parameters predictive of disease progression; time to treatment; and survival. [Cancers] Full Article

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Selective Autophagy in Normal and Malignant Hematopoiesis

The authors focus on the emerging evidence supporting an important role of selective autophagy in regulating normal hematopoiesis. They also cover aspects of selective autophagy pathways affected in the development and progression of leukemia and lymphoma. A molecular understanding of the unique requirements of selective autophagy may open new avenues for specific therapeutic intervention. [J Mol Biol] Abstract | Graphical Abstract

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

SpringWorks Therapeutics Announces Global Clinical Collaboration with GlaxoSmithKline to Evaluate Nirogacestat in Combination with Belantamab Mafodotin in Patients with Relapsed or Refractory Multiple Myeloma

SpringWorks Therapeutics, Inc. announced that the company has entered into a clinical trial collaboration agreement with GlaxoSmithKline to evaluate SpringWorks Therapeutics’ investigational gamma secretase inhibitor, nirogacestat, in combination with GlaxoSmithKline’s investigational anti-B-cell maturation antigen antibody-drug conjugate, belantamab mafodotin, in patients with relapsed or refractory multiple myeloma. [SpringWorks Therapeutics, Inc.] Press Release

Incyte and Zai Lab Announce Collaboration and License Agreement for INCMGA0012 in Greater China

Incyte and Zai Lab Ltd. announced that the companies have entered into a collaboration and license agreement for the development and commercialization of INCMGA0012, an investigational anti-PD-1 monoclonal antibody, in Greater China. [Incyte Corporation] Press Release

Precigen Announces First Patient Dosed in Phase I/Ib Study of PRGN-3006 UltraCAR-T™ in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) or Higher Risk Myelodysplastic Syndrome (MDS)

Precigen, Inc. announced that the first patient has been dosed with PRGN-3006, a first-in-class investigational therapy using Precigen’s non-viral UltraCAR-T™ therapeutic platform. [Precigen, Inc. (PR Newswire Association LLC.)] Press Release

Janssen Receives Positive CHMP Opinion Recommending Expanded Use of Imbruvica^® (Ibrutinib) in Two Indications in Europe

One recommendation is for the use of ibrutinib in combination with obinutuzumab in adult patients with previously untreated chronic lymphocytic leukemia. The second is for use of ibrutinib plus rituximab for the treatment of adult patients with Waldenström’s macroglobulinemia. [Janssen Pharmaceutica N.V.] Press Release

Genmab Announces US FDA Approval of DARZALEX^® (Daratumumab) in Combination with Lenalidomide and Dexamethasone in Frontline Multiple Myeloma

Genmab A/S announced that the FDA has approved the use of DARZALEX^® in combination with lenalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. [Genmab A/S] Press Release

NMPA Accepts New Drug Application for IBI301, a Biosimilar Product Candidate of Rituximab (MabThera/Rituxan)

Innovent Biologics, Inc. and Eli Lilly and Company jointly announced that the National Medical Products Administration (NMPA) has accepted its new drug application for IBI301, a co-developed biosimilar product candidate of rituximab. [Innovent Biologics, Inc.] Press Release

Kiadis Updates Status of Marketing Authorization Application for ATIR101

Kiadis Pharma N.V. announced that it has received feedback from the European Medicines Agency related to the marketing authorization application seeking approval of ATIR101 in hematopoietic stem cell transplant. [Kiadis Pharma N.V.] Press Release

MMRF Launches Leading-Edge Immune Atlas Initiative

The Multiple Myeloma Research Foundation (MMRF) announced that it is piloting a new precision medicine research initiative called the Immune Atlas. The objectives of this Immune Atlas pilot are to develop a ‘gold standard’ immune profiling platform for myeloma research studies and to generate robust immune data that is fundamental to the delivery of precision medicine. [The Multiple Myeloma Research Foundation] Press Release

India Culls Hundreds More ‘Dubious’ Journals From Government Approved List

A rise in Indian scientists publishing research in low-quality journals prompted the University Grants Commission to create a ‘white list’ of approved journals in 2017. Universities use the list to evaluate researchers for promotion and hiring. [Nature News] Editorial

Germany’s Prestigious Max Planck Society Conducts Huge Bullying Survey

Most of the scientists who work for one of the world’s richest and most prestigious basic research organizations, the Max Planck Society (MPS) in Germany, have pride and trust in their institutes — but cases of sexual discrimination and bullying occur regularly, and nearly half of foreign scientists working for the MPS don’t feel they fit in. [Nature News] Editorial

NEW EMBL Conference: Cancer Genomics
November 4-6, 2019
Heidelberg, Germany

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

NEW Postdoctoral Researcher – Hematopoietic Stem Cell Biology (Imperial College London)

NEW Faculty Positions – Center for Childhood Cancer and Blood Diseases (The Research Institute at Nationwide Children’s Hospital)

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

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

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)

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