Hematopoiesis News Volume 10.26 | Jul 9 2019

TOP STORY

Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia

Resistance to mubritinib characterized normal CD34⁺ hematopoietic cells and chemotherapy-sensitive acute myeloid leukemias (AMLs), which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation hyperactivity. [Cancer Cell] Abstract | Press Release

(Ranked by impact factor of the journal)

PRDM16s Transforms Megakaryocyte-Erythroid Progenitors to Acute Myeloid Leukemia-Initiating Cells

Researchers showed that the transcriptional regulator PRDM16s caused oncogenic fate conversion by transforming cells fated to form platelets and erythrocytes into myeloid leukemia stem cells (LSCs). Prdm16s expression in megakaryocyte-erythroid progenitors (MEPs), which normally lack the potential to generate granulo-monocytic cells, caused AML by converting MEPs to LSCs. [Blood] Abstract

Adult Stem Cell Deficits Drive Slc29a3 Disorders in Mice

Scientists identified adult stem cell deficits that drove equilibrative nucleoside transporter 3 (ENT3)-related abnormalities in mice. ENT3 deficiency altered hematopoietic and mesenchymal stem cell fates; the former led to stem cell exhaustion, and the latter led to breaches of mesodermal tissue integrity. [Nat Commun] Full Article

Nbn-Mre11 Interaction Is Required for Tumor Suppression and Genomic Integrity

Nbn^−/mid8vav mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within six months, Nbn^−/mid8vav mice developed highly penetrant T cell leukemias. [Proc Natl Acad Sci USA] Abstract

Deletion of the Miz-1 POZ Domain Increases Efficacy of Cytarabine Treatment in T- and B-ALL/Lymphoma Mouse Models

Investigators showed that ablation of the function of the BTB/POZ domain factor Miz-1, an important co-factor of c-Myc, significantly delayed T- and B-acute lymphoblastic leukemia (ALL)/lymphoma in mice and interfered with the oncogenic transcriptional activity of c-Myc. Leukemic cells that still emerged in this system activated DNA replication pathways that could be targeted by current chemotherapeutic drugs such as cytarabine. [Cancer Res] Abstract

Overcoming Tyrosine Kinase Inhibitor Resistance in Transformed Cell Harboring SEPT9-ABL1 Chimeric Fusion Protein

Mouse TP53 homologue TRP53 was downregulated and less phosphorylated in the cells expressing SEPT-ABL1 than in those with BCR-ABL1, resulting in the prevention of apoptosis induced by tyrosine kinase inhibitors. The CRM1 inhibitor KPT-330 accumulated nuclear TRP53 and NFKB1A, which was thought to capture TRP53 in the cytoplasm, and induced apoptosis in the hematopoietic cells expressing SEPT9-ABL1. [Neoplasia] Full Article

Reversine Exhibits Antineoplastic Activity in JAK2^V617F-Positive Myeloproliferative Neoplasms

The impact of ruxolitinib treatment on cytoskeleton-related genes expression was explored. In SET2 cells, AURKA and AURKB expression/activity were downregulated in a dose- and time-dependent manner by ruxolitinib. Reversine, a multikinase inhibitor selective for aurora kinases, reduced cell viability in a dose- and/or time-dependent manner in JAK2^V617F cells. [Sci Rep] Full Article

CLINICAL RESEARCH

Impact of Treatment with Iron Chelation Therapy in Patients with Lower-Risk Myelodysplastic Syndromes Participating in the European MDS Registry

Researchers assessed the effect of iron chelation on overall survival and hematological improvement in lower-risk myelodysplastic syndrome patients in the European MDS registry. They compared chelated patients with a contemporary, non-chelated control group within the European MDS registry that met the eligibility criteria for starting iron chelation. [Haematologica] Abstract

First-in-Human Trial of rhIL-15 and Haploidentical Natural Killer Cell Therapy for Advanced Acute Myeloid Leukemia

In vivo expansion of haploidentical natural killer (NK) cell infusions with interleukin-2 (IL-2) can induce remission of refractory acute myeloid leukemia, but efficacy may be hampered by concurrent stimulation of host regulatory T cells. To overcome this limitation, scientists substituted the NK homeostatic factor IL-15 in two Phase I/II trials. [Blood Adv] Abstract | Graphical Abstract

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Chronic Lymphocytic Leukemia: From Genetics to Treatment

The authors discuss new insights into the genetic lesions involved in the pathogenesis of chronic lymphocytic leukemia and how these genetic insights influence clinical management and the development of new therapeutic strategies for this disease. [Nat Rev Clin Oncol] Abstract

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

Catalyst Biosciences Meets the Primary Endpoint of Reduction in Annualized Bleeding Rate in the Phase II Trial of Subcutaneous Marzeptacog Alfa (Activated) in Patients with Hemophilia A or B with Inhibitors

Catalyst Biosciences, Inc. announced that the Phase II trial of its subcutaneous Factor VIIa variant marzeptacog alfa for prophylaxis met the primary endpoint of significantly reducing the annualized bleed rate in patients with hemophilia A or B with inhibitors. [Press release from Catalyst Biosciences, Inc. discussing research presented at the 2019 Congress of the International Society on Thrombosis and Haemostasis, Melbourne] Press Release

Cellect Biotechnology and Washington University (WU) Finalize Accelerated Clinical Trial Agreement

As the two organizations move closer to the commencement of the clinical trial to determine the safety and tolerability of the Apograft technology for bone marrow transplantations, Cellect Biotechnology Ltd. and Washington University announced the signing of an Accelerated Clinical Trial Agreement. [Cellect Biotechnology Ltd. (PR Newswire Association LLC.)] Press Release

Genmab Announces Positive Topline Results in the Phase II GRIFFIN Study of Transplant Eligible, Newly Diagnosed Patients with Multiple Myeloma Treated with Daratumumab in Combination with Lenalidomide, Bortezomib, and Dexamethasone

Genmab A/S announced that topline data from the Phase II GRIFFIN study of newly diagnosed patients with multiple myeloma eligible for high-dose chemotherapy and autologous stem cell transplantation, who were treated with daratumumab in combination with lenalidomide, bortezomib, and dexamethasone (VRd), met its primary endpoint, demonstrating a higher percentage of stringent complete responses than patients who received VRd alone. [Genmab A/S] Press Release

Bellicum Pharmaceuticals Announces Rivo-Cel™ Achieves Primary Endpoint in Pediatric Registrational Trial

Bellicum Pharmaceuticals, Inc. announced that the primary endpoint of event free survival at 180 days in its BP-004 European registration trial for rivo-cel has been achieved. Data from this trial will form the basis of an anticipated submission of European Marketing Authorization Applications for rivo-cel and rimiducid in support of potential regulatory approval. [Bellicum Pharmaceuticals, Inc.] Press Release

Karyopharm Announces FDA Approval of XPOVIO™ (Selinexor) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma

Karyopharm Therapeutics Inc. announced that the FDA has approved oral XPOVIO™, a nuclear export inhibitor, in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. [Karyopharm Therapeutics Inc.] Press Release

Cellectar Receives FDA Fast Track Designation for CLR 131 in Diffuse Large B-Cell Lymphoma

Cellectar Biosciences, Inc. announced the FDA has granted Fast Track Designation for CLR 131 in relapsed or refractory diffuse large B-cell lymphoma. CLR 131 is the company’s small-molecule, cancer-targeting radiotherapeutic Phospholipid Drug Conjugate™ designed to deliver cytotoxic radiation directly and selectively to cancer cells and cancer stem cells. [Cellectar Biosciences, Inc.] Press Release

Can Red Cell Exchange Treat Advanced Sickle Cell Disease?

Researchers at the University of Pittsburgh and UPMC, supported by a $19.2 million National Institutes of Health grant, will lead the largest clinical trial of its kind to test a technique called red cell exchange transfusion in prolonging life and slowing or reversing organ damage. [University of Pittsburgh] Press Release

Scandal-Weary Swedish Government Takes Over Research-Fraud Investigations

Bruised by a string of high-profile scientific-misconduct cases, Sweden has laid the legislative groundwork for a government agency that will handle all allegations of serious research misconduct. The country follows in the footsteps of neighboring Denmark, which created the world’s first such agency in 2017. [Nature News] Editorial

Hungarian Government Takes Control of Research Institutes despite Outcry

After months of struggle between Hungary’s research ministry and its scientific community, the nation’s parliament ratified a law on 2 July that gives the government control over the 40 or so institutes belonging to the Hungarian Academy of Sciences. The government says that its aim is to make research more innovative. [Nature News] Editorial

Stem Cell Funding Agency CIRM Is Nearly out of Funds

After funding stem cell research since 2004, the California Institute for Regenerative Medicine is running out of funds. The state agency currently has funding requests for $88 million pending but only $33 million left to give out to scientists. [The Scientist] Editorial

NEW 7^th International Conference on Stem Cell Engineering 2019
December 11-13, 2019
Barcelona, Spain

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

NEW Postdoctoral Fellow – Acute Myeloid Leukemia Research (University of Gothenburg)

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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