Hematopoiesis News Volume 8.10 | Mar 14 2017

TOP STORY

Functional Selectivity in Cytokine Signaling Revealed through a Pathogenic EPO Mutation

Investigators describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. [Cell] Abstract | Graphical Abstract

(Ranked by impact factor of the journal)

Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion but can be toxic when administered in vivo because it concurrently activates mast cells. Scientists engineered a mechanism-based SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. [Cell] Abstract | Graphical Abstract

ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

The authors demonstrated that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. [Cancer Cell] Abstract | Graphical Abstract

Regulation of PI3K Signaling in T Cell Acute Lymphoblastic Leukemia: A Novel PTEN/Ikaros/miR-26b Mechanism Reveals a Critical Targetable Role for PIK3CD

PTEN is a tumor suppressor that inactivates the PI3K pathway. Researchers profiled miRNAs in Pten-deficient mouse T-ALL and identified miR-26b as a potentially dysregulated gene. They validated decreased expression levels of miR-26b in mouse and human T-ALL cells. [Leukemia] Abstract

High mTORC1 Activity Drives Glycolysis Addiction and Sensitivity to G6PD Inhibition in Acute Myeloid Leukemia Cells

Investigators decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). They showed that mTORC1 signaling which is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. [Leukemia] Abstract

Inhibition of Pol I Transcription Treats Murine and Human AML by Targeting the Leukemia-Initiating Cell Population

Researchers reveal that the selective inhibitor of RNA Polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive acute myeloid leukemia (AML), including MLL-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461, the induction of p53-dependant apoptotic cell death, inhibition of Pol I transcription also demonstrated potent efficacy in p53^null AML in vivo. [Blood] Abstract

NF-κB p50 Activation Associated with Immune Dysregulation Confers Poorer Survival for Diffuse Large B-Cell Lymphoma Patients with Wild-Type p53

Scientists analyzed the prognostic significance and gene expression signatures of p50 nuclear expression as a surrogate for p50 activation in 465 patients with de novo diffuse large B-cell lymphoma. [Mod Pathol] Abstract

Erythro-Myeloid Progenitors Can Differentiate from Endothelial Cells and Modulate Embryonic Vascular Remodeling

Investigators provide the first evidence in vivo that erythro-myeloid progenitors (EMPs) can emerge directly from endothelial cells (ECs) and demonstrated a role for these cells in vascular development. They found that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein, as ECs do. [Sci Rep] Full Article

CLINICAL RESEARCH

Successful Transfer of Umbilical Cord Blood CD34⁺ Hematopoietic Stem and Progenitor-Derived NK Cells in Older Acute Myeloid Leukemia Patients

The authors report the first-in-human study exploiting an unique scalable natural killer (NK) cell product generated ex vivo from CD34⁺ hematopoietic stem and progenitor cells from partially HLA-matched umbilical cord blood units. [Clin Cancer Res] Abstract

A Phase I/II Study of Chemosensitization with Plerixafor plus G-CSF in Relapsed or Refractory Acute Myeloid Leukemia

Scientists hypothesized that disruption of the interaction between leukemic blasts with the marrow microenvironment using granulocyte-colony stimulating factor (G-CSF) in combination with plerixafor would effectively mobilize and sensitize acute myeloid leukemia blasts to chemotherapy. [Blood Cancer J] Full Article

Mesenchymal Stromal Cell Infusion to Treat Steroid-Refractory Acute GvHD III/IV after Hematopoietic Stem Cell Transplantation

The authors report the results of 46 patients treated with mesenchymal stromal cell (MSC) infusion as salvage therapy for steroid-refractory acute GvHD (aGvHD) III/IV. Patients received a median cumulative dose of MSCs of 6.81 × 10⁶/kg in a median of three infusions. Median time between the onset of aGvHD and the first MSC infusion was 25.5 days. [Bone Marrow Transplant] Abstract

Autologous Hematopoietic Stem Cell Transplantation in Systemic Lupus Erythematosus and Antiphospholipid Syndrome: A Systematic Review

The authors systematically review the literature and analyze the available evidence on hematopoietic stem cell transplantation therapy in patients with systemic lupus erythematosus and antiphospholipid syndrome, with a focus on therapy efficacy and occurrence of adverse events. [Autoimmun Rev] Abstract

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

Servier and Pfizer Announce FDA Clearance of IND Application for UCART19 in Adult Relapsed/Refractory Acute Lymphoblastic Leukemia

Servier, together with Pfizer Inc. and Cellectis announced that the U.S. Food and Drug Administration (FDA) has granted Servier with an Investigational New Drug (IND) clearance to proceed in the U.S. with the clinical development of UCART19, an allogeneic, gene-edited cellular therapy candidate to treat relapsed/refractory acute lymphoblastic leukemia. [Pfizer Inc.] Press Release

FDA Grants Orphan Drug Designation to Boehringer Ingelheim’s Investigational Anti-CD33 Monoclonal Antibody BI 836858 for Treatment of Myelodysplastic Syndromes

Boehringer Ingelheim announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to its anti-CD33 monoclonal antibody BI 836858 for the treatment of myelodysplastic syndromes. Orphan drug designation is granted by the FDA to investigational compounds intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people. [Boehringer Ingelheim Pharmaceuticals, Inc. (PR Newswire Association LLC.)] Press Release

U.K. Scientists Prepare for Impending Break with European Union

For months after the United Kingdom (U.K.) voted last June to leave the European Union (EU), many British scientists clung to hopes of a “soft Brexit,” which would not cut them off from EU funding and collaborators. But Prime Minister Theresa May, who is expected to trigger the two-year process of exiting the European Union, has signaled the break will be sharp. U.K. [ScienceInsider] Editorial

Canada’s New Genetic Privacy Law Is Causing Huge Headaches for Justin Trudeau

A vote in Canada’s Parliament to approve a genetic privacy bill is creating a self-inflicted political headache for Prime Minister Justin Trudeau’s Liberal government—and could result in a relatively rare and unusual court case. [ScienceInsider] Editorial

Physician with Drug-Industry Ties Is Trump’s FDA Pick

President Donald Trump has nominated Scott Gottlieb — a conservative pundit, physician and venture capitalist — to head the US Food and Drug Administration (FDA). [Nature News] Editorial

NEW NYSTEM 2017
May 11-12, 2017
New York City, United States

NEW Mitochondrial Biogenesis and Dynamics in Health, Disease and Aging
May 21-26, 2017
West Palm Beach, United States

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

NEW Principal Scientist – Immuno Oncology (Celgene Corporation)

Full Professor – Director of Stem Cell Transplantation (Dana Farber/Boston Children’s Cancer and Blood Disorders Center)

Postdoctoral Position – Hematopoietic Stem Cell Biology (Inserm)

Postdoctoral/Assistant Scientist – Epigenetic Regulation in Normal and Malignant Hematopoiesis (University of Florida)

Postdoctoral Fellow – Stem Cell and Leukemia Program (City of Hope)

Postdoctoral Fellow – Human Genome Editing (Johns Hopkins University School of Medicine)

Principal Scientist – Translational Development, Myeloid Disease Strategy (Celgene Corporation)

Senior Scientist – Translational and Diagnostic Informatics (Celgene Corporation)

Postdoctoral Fellow – Hematopoietic Gene Regulation and Leukemia (Boston Children’s Hospital and Harvard Medical School)

Postdoctoral Researcher – Genetic Alterations Involved in the Development, Maintenance and Relapse of Acute Leukemia (University of Basel)

Postdoctoral Fellow – Age Associated Changes of the Hematopoietic Stem Cell Compartment (National Institutes of Health / National Institute on Aging)

Research Specialist – Metabolomics Methods to Stem Cell Metabolism (Howard Hughes Medical Institute)

Principal Scientist – Translational Development (Celgene Corporation)

Associate Director – Translational Development (Celgene Corporation)

Assistant Professor – Molecular Therapeutics of Cancer (Dartmouth College)

Postdoctoral Fellow – Hematopoietic Development and Homeostasis (Harvard Medical School, BIDMC)

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