Hematopoiesis News Volume 7.49 | Dec 13 2016

TOP STORY

A 17-Gene Stemness Score for Rapid Determination of Risk in Acute Leukemia

To develop predictive and/or prognostic biomarkers related to stemness, researchers generated a list of genes that are differentially expressed between 138 leukemia stem cells (LSC)⁺ and 89 LSC⁻ cell fractions from 78 acute myeloid leukemia patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, they performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score. [Nature] Abstract | Press Release

(Ranked by impact factor of the journal)

Fasting Selectively Blocks Development of Acute Lymphoblastic Leukemia via Leptin-Receptor Upregulation

The authors report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia, but not acute myeloid leukemia, in mouse models of these tumors. [Nat Med] Abstract | Press Release

Loss of the Histone Methyltransferase EZH2 Induces Resistance to Multiple Drugs in Acute Myeloid Leukemia

Scientists identified loss of the histone methyltransferase EZH2 and subsequent reduction of histone H3K27 trimethylation as a novel pathway of acquired resistance to tyrosine kinase inhibitors and cytotoxic drugs in acute myeloid leukemia (AML). Low EZH2 protein levels correlated with poor prognosis in AML patients. Suppression of EZH2 protein expression induced chemoresistance of AML cell lines and primary cells in vitro and in vivo. [Nat Med] Abstract

Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway

The authors purified recombinant Fanconi anemia (FA) core complex to reveal the function of these other proteins. The complex contained two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE acted as substrate receptors and restricted monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form. [Mol Cell] Abstract | Graphical Abstract

Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation

To uncover the basis for infection-associated bone marrow suppression, investigators conducted repeated infection of WT mice with Mycobacterium avium. After 4–6 months, mice became pancytopenic. Their hematopoietic stem and progenitor cells were severely depleted and displayed interferon gamma signaling-dependent defects in self-renewal. [Cell Rep] Full Article | Press Release | Graphical Abstract

The FA Core Complex Contains a Homo-Dimeric Catalytic Module for the Symmetric Mono-Ubiquitination of FANCI-FANCD2

Researchers used structural electron microscopy, combined with crosslink-coupled mass spectrometry, to find that FANCB, FANCL, and FAAP100 form a dimer of trimers, containing two FANCL molecules that are ideally poised to target both FANCI and FANCD2 for mono-ubiquitination. The FANCC-FANCE-FANCF subunits bridge between FANCB-FANCL-FAAP100 and the FANCI-FANCD2 substrate. [Cell Rep] Full Article | Graphical Abstract

USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells

Investigators found that ubiquitin-specific peptidase 10 (USP10) is a crucial deubiquitinase for mouse hematopoiesis. All USP10 knockout (KO) mice died within one year because of bone marrow failure with pancytopenia. Bone marrow failure in these USP10-KO mice was associated with remarkable reductions of long-term hematopoietic stem cells in bone marrow and fetal liver. [Stem Cell Reports] Full Article

Sensitivity of Hematopoietic Stem Cells to Mitochondrial Dysfunction by SdhD Gene Deletion

Given that hematopoietic stem cells metabolism is essentially oxygen-independent, it is still unclear whether functional mitochondria are absolutely required for their survival. To assess the actual dependency of these undifferentiated cells on mitochondrial function, the authors have performed an analysis of the hematopoiesis in a mouse mutant, named SDHD-ESR, with inducible deletion of the mitochondrial protein-encoding SdhD gene. [Cell Death Dis] Full Article

Preclinical Validation: LV/IL-12 Transduction of Patient Leukemia Cells for Immunotherapy of AML

Investigators carried out preclinical validation studies using a novel lentivector to engineer expression of human Interleukin-12 (IL-12) in acute myeloid leukemia blast cells isolated from 21 patients. Acute myeloid leukemia cells were transduced with a bicistronic lentivector that encodes the human IL-12 cDNA as a fusion, as well as a LNGFR (ΔLNGFR)/mutant thymidylate kinase cassette as a marking and cell-fate control element. [Mol Ther Methods Clin Dev] Full Article

CLINICAL RESEARCH

Individualized Vaccination of AML Patients in Remission Is Associated with Induction of Antileukemia Immunity and Prolonged Remissions

Researchers report results obtained from the first 17 acute myeloid leukemia (AML) patients, who achieved remission after chemotherapy and were then serially vaccinated to target minimal residual disease and prevent relapse. Vaccination was well tolerated and induced inflammatory responses at the site of administration, characterized by the dense infiltration of T cells. [Sci Transl Med] Abstract

Sensing Danger: Toll-Like Receptors and Outcome in Allogeneic Hematopoietic Stem Cell Transplantation

Based mainly on animal studies there is growing evidence to suggest that Toll-like receptors are involved in the development of chemotherapy-induced mucositis and in the propagation of graft versus host reactions as well as graft versus tumor effects in allogeneic hematopoietic stem cell transplantation (HSCT). The authors discuss these findings along with the emerging, although still preliminary, clinical evidence, that points to a role of pattern recognition receptors in determining the outcome of HSCT and new therapeutic perspectives that may be related to this development. [Bone Marrow Transplant] Abstract

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

Kiadis Pharma Presents Positive 1-Year Follow-Up Data of Its Pivotal Phase II Trial With ATIR101™

Kiadis Pharma N.V. presents positive one-year data with its lead product ATIR101^™ from the single dose Phase II trial. Dr. Denis-Claude Roy, Professor of Medicine at the University of Montreal, one of the principal investigators for the trial and protocol chair, confirms that ATIR101^™ can be safely infused and shows a significant reduction in Transplant Related Mortality and a significant improvement in Overall Survival in comparison to an observational control group of patients undergoing a T-cell depleted haploidentical donor transplantation only. [Press release from Kiadis Pharma N.V. discussing research presented at 58^th Annual Meeting and Exposition of the American Society of Hematology (ASH), San Diego] Press Release

Moffitt CEO Dr. Alan List Awarded Celgene 2016 Career Achievement Award for Clinical Research in Hematology

Moffitt Cancer Center President and CEO Alan F. List, M.D., has been awarded the Celgene 2016 Career Achievement Award for Clinical Research in Hematology. The award recognizes List for his tremendous impact and significant contributions in the field of clinical hematology throughout his career. The Celgene Corporation will provide a $25,000 grant to Moffitt in List’s name in honor of the award. [Moffitt Cancer Center] Press Release

EMBO Installation Grants to Support Ten Researchers in Establishing Laboratories

Ten life scientists have been awarded EMBO Installation Grants to set up independent research laboratories in the Czech Republic, Estonia, Poland, Portugal and Turkey. Installation Grants are awarded annually. They are funded primarily by the participating member states Czech Republic, Estonia, Poland, Portugal and Turkey. Grantees are selected by a committee of EMBO Members on the basis scientific excellence as the primary selection criterion. [European Molecular Biology Organization (EMBO)] Press Release

Sutro ADC Targeting CD74 Exhibits Potent Anti-Tumor Activity in Multiple Malignant Cell Lines and Animal Models of Non-Hodgkin Lymphoma and Multiple Myeloma

Sutro Biopharma Inc. announced that it has launched IND-enabling studies, including preparation for GLP toxicology, of STRO-001, an antibody drug conjugate, or ADC, that targets CD74, a protein highly expressed in B-cell malignancies. STRO-001 demonstrated efficient cell killing in multiple malignant B-cell lines and exhibited potent anti-tumor activity in six mouse tumor models of non-Hodgkin lymphoma and multiple myeloma, according to studies recently completed by Sutro. [Sutro Biopharma Inc.] Press Release

Brexit by the Numbers: The Fear of Brain Drain

British universities fear losing large swathes of their research staff as the country faces up to Brexit, the split with the European Union. More than 31,000 academics at UK universities are non-British EU citizens, and so may lose their rights to live in the United Kingdom after Brexit. [Nature Trend Watch] Editorial

Italian Scientists Won’t Miss Departing Prime Minister Matteo Renzi

Italian politics is in turmoil after the resignation of Prime Minister Matteo Renzi — but researchers say that they are not particularly sad to see him go. In his almost three years in charge, Renzi promised improvements for universities and science but failed to raise the status of research in the country, according to scientists who complain that he also directly interfered in academic affairs. [Nature News] Editorial

NEW 29^th Lorne Cancer Conference
February 9-11, 2017
Lorne, Australia

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

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

NEW Postdoctoral Fellow – Self-Renewal and Differentiation of Hematopoietic Stem Cells (Boston Children’s Hospital; Harvard Medical School)

Research Technologist – Hematopoietic Product Development (STEMCELL Technologies)

Postdoctoral Fellowship – Pharmaceutics/Cancer Biology (Ohio State University)

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)

Postdoctoral Fellowship – Stem Cell and Red Cell Biology (Lund University)

Postdoctoral Fellow(s) – Various Projects (Cincinnati Children’s Hospital Medical Center)

Research Associate – Hematology (Editas Medicine)

Postdoctoral Position – Hematology and Gene Therapy (Cincinnati Children’s Research Foundation)

Postdoctoral Position – Leukemia and Marrow Failure (H. Leighton Grimes)

Postdoctoral Position – Experimental Hematology and Cancer Biology (Cincinnati Children’s Research Foundation)

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