Hematopoiesis News Volume 10.11 | Mar 26 2019

TOP STORY

FDA-Approved Ferumoxytol Displays Anti-Leukemia Efficacy against Cells with Low Ferroportin Levels

Using leukemia cell lines and primary acute myeloid leukemia patient samples, researchers showed that low expression of the iron exporter ferroportin resulted in a susceptibility of these cells via an increase in intracellular iron from ferumoxytol. The reactive oxygen species produced by free ferrous iron led to increased oxidative stress and cell death. [Nat Nanotechnol] Abstract | Press Release

(Ranked by impact factor of the journal)

Highly Efficient Therapeutic Gene Editing of Human Hematopoietic Stem Cells

Scientists optimized conditions for selection-free on-target editing in patient-derived HSCs as a nearly complete reaction lacking detectable genotoxicity or deleterious impact on stem cell function. Erythroid progeny of edited engrafting sickle cell disease HSCs expressed therapeutic levels of HbF and resisted sickling, while those from patients with β-thalassemia showed restored globin chain balance. [Nat Med] Abstract

Precise Gene Editing Preserves Hematopoietic Stem Cell Function Following Transient p53-Mediated DNA Damage Response

p53-mediated DNA damage response pathway activation was the predominant response to even single-nuclease-induced DNA double-stranded breaks (DSBs) across all hematopoietic stem and progenitor cells (HSPCs) subtypes analyzed. Excess DSB load and/or adeno-associated virus-mediated delivery of DNA repair templates induced cumulative p53 pathway activation, constraining proliferation, yield, and engraftment of edited HSPCs. [Cell Stem Cell] Full Article | Press Release | Graphical Abstract

Mesenchymal Niche-Specific Expression of Cxcl12 Controls Quiescence of Treatment-Resistant Leukemia Stem Cells

Investigators showed that targeted deletion of Cxcl12 from mesenchymal stromal cells reduced normal HSC numbers but promoted leukemic stem cell (LSC) expansion by increasing self-renewing cell divisions, possibly through enhanced Ezh2 activity. In contrast, endothelial cell-specific Cxcl12 deletion decreased LSC proliferation, suggesting niche-specific effects. [Cell Stem Cell] Abstract | Press Release | Graphical Abstract

Gfi1b Regulates the Level of Wnt/β-Catenin Signaling in Hematopoietic Stem Cells and Megakaryocytes

Numerous canonical Wnt/β-catenin target genes, co-occupied by Gfi1b, β-catenin and LSD1, had their expression deregulated in Gfi1b-deficient cells. When Gfi1b-deficient cells were treated with Wnt3a, their normal cellularity was restored and Gfi1b-deficient megakaryocytes regained their ability to spread on integrin substrates. [Nat Commun] Full Article

PLZF Limits Enhancer Activity during Hematopoietic Progenitor Aging

Functional analyses revealed that active enhancers bound by promyelocytic leukemia zinc finger (PLZF) were involved in biological processes related to metabolism and associated with hematopoietic aging. Comparing the epigenome of young and old myeloid progenitors, the authors revealed that H3K27ac variation at active enhancers was a hallmark of hematopoietic aging. [Nucleic Acids Res] Full Article

Biology and Prognostic Impact of Clonal Plasmacytoid Dendritic Cells in Chronic Myelomonocytic Leukemia

Whole-exome sequencing of sorted monocytes and plasmacytoid dendritic cells (pDCs) identified somatic mutations in genes of the oncogenic RAS pathway in the two cell types of every patient. CD34⁺ cells could generate high amount of pDCs in the absence of FMS-like tyrosine kinase 3-ligand. Finally, an excess of pDCs correlated with regulatory T cell accumulation and an increased risk of acute leukemia transformation. [Leukemia] Abstract

Inhibitory Effects of Midostaurin and Avapritinib on Myeloid Progenitors Derived from Patients with KIT D816V Positive Advanced Systemic Mastocytosis

The authors investigated the effects of the KIT-inhibitors midostaurin and avapritinib on single-cell-derived myeloid progenitor cells using granulocyte-macrophage colony-forming-units of patients with KIT D816V positive dvanced systemic mastocytosis. Colonies obtained prior to treatment were incubated in vitro with midostaurin or avapritinib and showed a marked reduction of KIT D816V positive colonies in 3/10 and 7/11 patient samples, respectively. [Leukemia] Full Article

Nidogen-1 Contributes to the Interaction Network Involved in Pro-B Cell Retention in the Peri-Sinusoidal Hematopoietic Stem Cell Niche

Preferential contacts were found between pro-B cells and peri-sinusoidal stromal cells, which homogeneously expressed HSC and B cell niche genes. Furthermore, pro-B cells were frequently located in the vicinity of HSCs in the same niche. [Cell Rep] Full Article | Graphical Abstract

Enhanced Renewal of Erythroid Progenitors in Myelodysplastic Anemia by Peripheral Serotonin

Researchers reveal a fundamental role for tryptophan metabolized along the serotonin pathway in normal erythropoiesis and in the physiopathology of myelodysplastic syndrome-related anemia. They identified, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. [Cell Rep] Full Article | Graphical Abstract

CLINICAL RESEARCH

Immune Signature Drives Leukemia Escape and Relapse after Hematopoietic Cell Transplantation

In two independent patient cohorts investigators confirmed the deregulation of multiple costimulatory ligands on acute myeloid leukemia blasts at post-transplantation relapse, mirrored by concomitant changes in circulating donor T cells. Likewise, they documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. [Nat Med] Abstract | Press Release

Distinct Mutation Spectrum, Clinical Outcome and Therapeutic Responses of Typical Complex/Monosomy Karyotype Acute Myeloid Leukemia Carrying TP53 Mutations

Scientists aimed to define a subtype of complex/monosomal karyotype (CK/MK) AML by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety-eight young adults with CK/MK AML were studied. They received standard induction, consolidation and allogeneic HSC transplantation from siblings or matched unrelated donors if available. [Am J Hematol] Abstract

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

Neutrophils as Regulators of the Hematopoietic Niche

The authors synthesize emerging concepts on niche regulation by immune cells, with a particular emphasis on neutrophils. They argue that the unique developmental, circadian and migratory properties of neutrophils underlie their critical contributions as regulators of the hematopoietic niche. [Blood] Abstract

CRISPR/Cas9-Modified Hematopoietic Stem Cells—Present and Future Perspectives for Stem Cell Transplantation

Investigators summarize the possibility of CRISPR/Cas9-mediated autologous HSC transplantation (HSCT) as a potential treatment option for various diseases supported by preclinical gene-editing studies. Furthermore, they discuss future clinical perspectives and possible clinical grade improvements of CRISPR/cas9-mediated autologous HSCT. [Bone Marrow Transplant] Abstract

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

Onconova Achieves over 75 Percent of Planned Enrollment in Pivotal Phase III INSPIRE Study of Rigosertib in Myelodysplastic Syndromes

Onconova Therapeutics, Inc. announced that it has surpassed the 75 percent enrollment milestone in its pivotal Phase III trial of rigosertib for the potential treatment of high-risk myelodysplastic syndromes, a study known as INSPIRE. [Onconova Therapeutics, Inc.] Press Release

Moleculin Announces Positive Interim Results in First Cohort of Phase I/II Clinical Studies of Annamycin in Acute Myeloid Leukemia in the US and in Poland

Moleculin Biotech, Inc. announced positive interim safety and efficacy data from two ongoing open label, single arm Phase I/II studies of Annamycin. In the first study, being conducted in the US, four patients have completed treatment at 100 mg/m² with no significant adverse events related to Annamycin, and the study will now proceed to the next higher dose of 120 mg/m². [Moleculin Biotech, Inc.] Press Release

First Cancer Patient Receives Dose of Super-Enhancer Inhibitor GZ17-6.02, an Advanced Cancer Drug from Genzada Pharmaceuticals, at HonorHealth Research Institute

Genzada Pharmaceuticals USA Inc. announced that the first patient enrolled in its Phase I clinical trial for the oral therapeutic GZ17-6.02 received the first dose this week at HonorHealth Research Institute in Scottsdale. Genzada’s GZ17-6.02 will be administered to patients with advanced solid cancers and lymphoma. [Genzada Pharmaceuticals USA Inc. (Business Wire, Inc.)] Press Release

Oxford Biomedica Notes the Japanese Approval of Kymriah^® (Tisagenlecleucel), the First CAR-T Cell Therapy Authorised in Asia

Oxford Biomedica plc noted an announcement by Novartis that Japan’s Ministry of Health, Labor and Welfare has approved Kymriah^® for the treatment of two distinct indications – CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia and CD19-positive r/r diffuse large B-cell lymphoma. [Oxford Biomedica plc] Press Release

Aptose Announces FDA Allowance of Investigational New Drug Application for CG-806

Aptose Biosciences Inc. has been granted IND allowance to initiate its Phase I clinical trial, which is a Phase I, multicenter, open label, dose-escalation study with expansions to assess the safety, tolerability, PK, and preliminary efficacy of CG-806 in patients with chronic lymphocytic leukemia or non-Hodgkin lymphomas. [Aptose Biosciences Inc.] Press Release

Selvita Announces U.S. FDA Acceptance of Investigational New Drug Application to Commence Clinical Development of sel120 in the Treatment of Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Selvita announced that the FDA has cleared its Investigational New Drug application to conduct a Phase I study of selective CDK8 inhibitor SEL120 in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. [Selvita] Press Release

Janssen Submits Application for DARZALEX® (Daratumumab) Combination Therapy to U.S. FDA for Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma

The Janssen Pharmaceutical Companies of Johnson & Johnson announced the submission of a supplemental Biologics License Application to the FDA seeking approval of DARZALEX in combination with bortezomib, thalidomide and dexamethasone for newly diagnosed patients with multiple myeloma who are eligible for autologous stem cell transplant. [Janssen Global Services, LLC] Press Release

Janssen Seeks Expanded Use of DARZALEX (Daratumumab) Combination Therapy for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant Ineligible

The Janssen Pharmaceutical Companies of Johnson & Johnson today announced the submission of a Type II variation application to the European Medicines Agency for DARZALEX in combination with lenalidomide and dexamethasone for the treatment of patients newly diagnosed with multiple myeloma who are ineligible for autologous stem cell transplant. [Janssen Global Services, LLC] Press Release

bluebird bio Statement on European Regulatory Status of LentiGlobin™

A third party press release was issued today stating that the European Medicines Agency issued an approval for the conditional Marketing Authorization Application for LentiGlobin™, bluebird bio’s investigational gene therapy for the treatment of transfusion dependent β-thalassemia. [bluebird bio, Inc.] Press Release

Innovative Cellular Therapeutics Announces Successful Completion of Pre-IND Meeting With FDA

Innovative Cellular Therapeutics (ICT) announced it has successfully completed a pre-Investigational New Drug (IND) meeting with the FDA. At the meeting, the FDA provided feedback regarding ICT’s planned initiation of clinical trials under a U.S. IND for its lead CAR-T candidate, ICTCAR014, for the treatment of Non-Hodgkin Lymphoma. [Innovative Cellular Therapeutics Co., Ltd.] Press Release

Duke University Settles Research Misconduct Lawsuit for $112.5 Million

Duke University will pay $112.5 million to the U.S. government to settle a lawsuit brought by a former employee who alleged that the university included falsified data in applications and reports for federal grants worth nearly $200 million. The university will also take several steps “to improve the quality and integrity of research conducted on campus,” including the creation of a new advisory panel that will provide recommendations to the president, the Durham, North Carolina, institution said in a statement. [ScienceInsider] Editorial

Top US Institutes Still Aren’t Reporting Clinical-Trial Results on Time

Many leading US universities are breaking the law by failing to make public the results of clinical trials. A report found that 25 of the 40 universities that sponsor the most trials in the United States did not post study results on a public, government register within 12 months of completion, as is required by US law. [Nature News] Editorial

As Elsevier Falters, Wiley Succeeds in Open-Access Deal Making

Over the last few years, Project DEAL, a consortium that represents around 700 academic institutions in Germany, has been in negotiations for nationwide licensing agreements with three of the largest scholarly publishers—Elsevier, Springer Nature, and Wiley. [The Scientist] Editorial

NEW International Society for Stem Cell Research (ISSCR) 2019 Annual Meeting
June 26-29, 2019
Los Angeles, California, United States

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

NEW 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)

Postdoctoral Studies Scholarship – Stem Cells & Erythropoiesis in MDS (Karolinska Institutet)

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)

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.