Hematopoiesis News Volume 10.13 | Apr 9 2019

TOP STORY

Cytokine Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis

Scientists demonstrated that hematopoietic cytokines phosphorylate TET2 leading to its activation in erythroid progenitors. Specifically, cytokine receptor associated, JAK2, phosphorylated TET2 at tyrosines 1939 and 1964. Phosphorylated TET2 interacted with erythroid transcription factor, KLF1, and this interaction with TET2 was increased upon exposure to erythropoietin. [Cancer Discov] Abstract | Full Article

(Ranked by impact factor of the journal)

Asrij/OCIAD1 Suppresses CSN5-Mediated p53 Degradation and Maintains Mouse Hematopoietic Stem Cell Quiescence

Molecular and biochemical analyses revealed increased polyubiquitinated protein levels, Akt/STAT5 activation and COP9 signalosome subunit 5 (CSN5)-mediated p53 ubiquitination and degradation in knockout hematopoietic stem/progenitor cells (HSPCs). Further, researchers showed that Asrij sequestered CSN5 via its conserved OCIA domain, thereby preventing p53 degradation. [Blood] Abstract

Gene Correction for SCID-X1 in Long-Term Hematopoietic Stem Cells

The authors describe an approach for X-linked severe combined immunodeficiency (SCID-X1) using targeted integration of a cDNA into the endogenous start codon to functionally correct disease-causing mutations throughout the gene. Using a CRISPR-Cas9/AAV6 based strategy, they achieved up to 20% targeted integration frequencies in long-term HSCs. [Nat Commun] Full Article

Identification of a Leukemia-Initiating Stem Cell in Human Mast Cell Leukemia

Scientists describe that leukemic stem cells in mast cell leukemia (MCL) reside within a CD34⁺/CD38⁻ fraction of the clone. Whereas highly purified D34⁺/CD38⁻ cells engrafted NSG_hSCF mice with fully manifesting MCL, no MCL was produced by D34⁺/CD38⁻ progenitors or the bulk of KIT⁺/CD34⁻ mast cells. [Leukemia] Full Article

Uniquely Human CHRFAM7A Gene Increases the Hematopoietic Stem Cell Reservoir in Mice and Amplifies Their Inflammatory Response

Investigators found that CHRFAM7A increased the HSC reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. They also observed that while the HSC reservoir was depleted in systemic inflammatory response syndrome, HSCs were spared in CHRFAM7A-transgenic mice and that these mice also had increased immune cell mobilization, myeloid cell differentiation, and a shift to inflammatory monocytes from granulocytes in their inflamed lungs. [Proc Natl Acad Sci USA] Full Article

PARI (PARPBP) Suppresses Replication Stress-Induced Myeloid Differentiation in Leukemia Cells

Researchers showed that PARI, a replisome protein involved in regulating DNA repair and replication stress, suppressed differentiation of myeloid leukemia cells. PARI depletion enhanced replication stress and DNA-damage accumulation, coupled with increased myeloid differentiation. [Oncogene] Abstract

PGE2 and Poloxamer Synperonic F108 Enhance Transduction of Human HSPC With a β-Globin Lentiviral Vector

Scientists found that transduction enhancers increased the in vitro vector copy number of bulk myeloid cultures ~10-fold while using a 10-fold lower lentiviral vector dose. This was accompanied by an increased percentage of transduced colony forming units. [Mol Ther Methods Clin Dev] Abstract | Full Article

A Human Hematopoietic Niche Model Supporting Hematopoietic Stem and Progenitor Cells In Vitro

Optimal hematopoietic stem and progenitor cell (HSPC) support was obtained in the presence of adipogenic and osteogenic cells, together with progenitor derived endothelial cells. When cultured in a bioactive hydrogel, the supportive cells self‐assembled into a hypoxic stromal network, stimulating CD34⁺CD38⁺ cell formation, while maintaining the pool of CD34⁺38⁻ HSPCs. [Adv Healthc Mater] Abstract | Press Release

CLINICAL RESEARCH

Enasidenib, an Inhibitor of Mutant IDH2 Proteins, Induces Durable Remissions in Older Patients with Newly Diagnosed Acute Myeloid Leukemia

Among 39 patients with newly diagnosed mutant-isocitrate dehydrogenase 2 (IDH2) acute myeloid leukemia who received enasidenib monotherapy in this Phase I/II trial, median age was 77 years and 23 patients had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0. The most common treatment-related adverse events were indirect hyperbilirubinemia, nausea, and fatigue, decreased appetite, and rash. [Leukemia] Full Article

Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia in the TKI Era: Population-Based Data From the Swedish CML Registry

Researchers investigated the indications for allogeneic stem cell transplantation, clinical outcome, management of relapse, and post-transplant tyrosine kinase inhibitor treatment in a population-based setting using the Swedish chronic myeloid leukemia (CML) registry. [Bone Marrow Transplant] Abstract

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Current Status of Autologous Stem Cell Transplantation for Multiple Myeloma

Who is most suited to undergo ASCT? Is there an age threshold that should not be surpassed? Should transplantation be embarked on early or is it reasonable to delay it? These are some of the questions addressed which the authors attempt to answer with the latest currently available data. [Blood Cancer J] Abstract

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

Tetraphase Pharmaceuticals Presents Preclinical Data on TP-2846, a Novel Drug Candidate for Acute Myeloid Leukemia

Tetraphase Pharmaceuticals, Inc. announced data from its preclinical program for TP-2846, the company’s new pipeline candidate for acute myeloid leukemia discovered using Tetraphase’s proprietary total synthesis platform. [Press release from Tetraphase Pharmaceuticals, Inc. discussing research presented at the 2019 American Association for Cancer Research (AACR) 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 2019 American Association for Cancer Research (AACR) Annual Meeting, Atlanta] Press Release

Genmab Announces Phase III Study Exploring Daratumumab as Maintenance Treatment in Newly Diagnosed Multiple Myeloma

The study will compare subcutaneous daratumumab in combination with lenalidomide versus lenalidomide alone as maintenance treatment in patients with newly diagnosed multiple myeloma who are minimal residual disease positive after frontline autologous stem cell transplant. [Genmab A/S] Press Release

Trovagene Announces Update to Phase Ib/II AML Trial Data Presented at AACR – Additional Patients Achieve Complete Response at Two Highest Dose Levels of Onvansertib

Additional data from its ongoing Phase Ib/II study evaluating onvansertib in combination with standard-of-care chemotherapy in acute myeloid leukemia (AML) demonstrates response to treatment in patients in the dose-escalation phase of the trial who received onvansertib at 27mg/m² and 40mg/m². [Trovagene, Inc.] Press Release

Sangamo Provides Clinical Development Update Including Early Phase I/II Beta Thalassemia Gene-Edited Cell Therapy Data

Sangamo Therapeutics, Inc. announced recent progress across its clinical portfolio, including early data for ST-400, an ex vivo gene-edited beta thalassemia cell therapy developed in partnership with Sanofi, and next steps for its in vivo genome editing programs. [Sangamo Therapeutics, Inc.] Press Release

Moleculin Announces Successful Expansion of Its Leukemia Drug Program

Moleculin Biotech, Inc. announced it has successfully expanded the clinical supply of Annamycin for its on-going clinical trials via BSP Pharmaceuticals S.p.A. in Italy. [Moleculin Biotech, Inc.] Press Release

PIXUVRI^® (Pixantrone) Receives Positive CHMP Opinion to Convert Conditional Approval Into Standard Marketing Authorization in Patients with Aggressive Non-Hodgkin B-Cell Lymphoma

Servier announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion for PIXUVRI^® to convert its conditional approval into a standard marketing authorization as a single agent for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphoma. [Servier (Business Wire, Inc.)] Press Release

GT Biopharma Receives Institutional Review Board Approval to Proceed With in Human FDA Phase I Clinical Trial

GT Biopharma, Inc. announced it has received authorization from the University of Minnesota’s Institutional Review Board and Cancer Protocol Review Committee that it can proceed with its planned TriKE Phase I clinical trial. [GT Biopharma, Inc.] Press Release

Celgene Corporation and Acceleron Pharma Announce Submission of Luspatercept Biologics License Application to US FDA

Celgene Corporation and Acceleron Pharma Inc. announced that Celgene has submitted a Biologics License Application for luspatercept, an erythroid maturation agent, for the treatment of adult patients with very low to intermediate risk myelodysplastic syndromes-associated anemia who have ring sideroblasts and require red blood cell (RBC) transfusions and for the treatment of adult patients with beta-thalassemia-associated anemia who require RBC transfusions. [Celgene Corporation] Press Release

Genmab Announces Submission of Supplemental New Drug Application in Japan for Daratumumab in Combination with Lenalidomide and Dexamethasone in Frontline Multiple Myeloma

Genmab A/S announced that Janssen Pharmaceutical K.K. has submitted a supplemental new drug application to the Ministry of Health, Labor and Welfare in Japan, for the use of daratumumab in combination with lenalidomide and dexamethasone as treatment for patients newly diagnosed with multiple myeloma who are not candidates for high-dose chemotherapy and autologous stem cell transplant. [Genmab A/S] Press Release

FDA Clears the IND for UCARTCS1, the First Allogeneic CAR-T to Treat Multiple Myeloma Patients

Cellectis announced that the FDA has approved the company’s Investigational New Drug (IND) application to initiate a Phase I clinical trial for UCARTCS1, in patients with multiple myeloma. [Cellectis] Press Release

Daiichi Sankyo’s EZH1/2 Dual Inhibitor Valemetostat (DS-3201) Receives SAKIGAKE Designation for Treatment of Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma From Japan MHLW

Daiichi Sankyo Company, Limited announced that valemetostat, an investigational and potential first-in-class EZH1/2 dual inhibitor, has received SAKIGAKE Designation for the treatment of adult patients with relapsed/refractory peripheral T-cell lymphoma by the Japan Ministry of Health, Labour and Welfare (MHLW). [Daiichi Sankyo Company, Limited] Press Release

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

Daiichi Sankyo Company, Limited announced that the FDA has extended the review period for the New Drug Application of quizartinib, an investigational FLT3 inhibitor, currently under Priority Review for the treatment of adult patients with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML). [Daiichi Sankyo Company, Limited] Press Release

Leading Myeloma Experts to Join New Center for Blood Cancers at NYU Langone Health

Nationally renowned hematology experts Gareth Morgan, MD, PhD, and Faith E. Davies, MD, are joining the Center for Blood Cancers at NYU Langone Health’s Perlmutter Cancer Center to lead its Multiple Myeloma Program. [NYU Langone Hospitals] Press Release

Racism Rife at Top South African University, Says Report

A damning report that says racism is entrenched at the University of Cape Town has reignited discussions about how to erase the divisive legacy of colonialism at South Africa’s top research institutions. [Nature News] Editorial

FDA, New York Attorney General Go After Stem Cell Clinics

On April 3, the FDA sent letters to 20 companies providing stem cell treatments, reports The New York Times, reminding them that they may require FDA approval and should take action to comply. The agency also issued a warning to a stem cell company for violating good manufacturing practices. [The Scientist] Editorial

coreSCD: Developing a Core Outcome Set for Sickle Cell Disease Clinical Research

The Green Park Collaborative is partnering with Sickle Cell Disease Association of America, Inc., to develop a core set of outcomes to be used in clinical trials of new therapies for sickle cell disease. [Center for Medical Technology Policy] Editorial

NEW 24^th Congress of the European Hematology Association (EHA)
June 13-16, 2019
Amsterdam, Netherlands

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

NEW Postdoctoral Fellows – Hematological Malignancies & Cancer Immunology (Fox Chase Cancer Center)

NEW 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)

Assistant Professor – Sarcoma or Skeletal Related Malignancies (University of California, Davis)

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

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

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