Hematopoiesis News Volume 8.04 | Jan 31 2017

TOP STORY

Pan-Mutant-IDH1 Inhibitor BAY1436032 Is Highly Effective against Human IDH1 Mutant Acute Myeloid Leukemia In Vivo

Scientists report the characterization of BAY1436032, a novel pan-mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits (R)-2-hydroxyglutarate production and colony growth, and induces myeloid differentiation of acute myeloid leukemia cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. [Leukemia] Abstract

(Ranked by impact factor of the journal)

Numerous Niches for Hematopoietic Stem Cells Remain Empty during Homeostasis

Investigators demonstrated that upon the transplantation of very large numbers of purified hematopoietic stem cells (HSCs) into normal mice not exposed to myeloablation, donor HSCs engrafted in niches distant from filled HSC niches without replacing host HSCs and subsequently proliferated and generated hematopoietic progenitors, leading to marked increases in the overall HSC number in bone marrow. [Blood] Abstract

MUC1 Mediated Induction of Myeloid-Derived Suppressor Cells in Patients with Acute Myeloid Leukemia

The authors demonstrated that patients with acute myeloid leukemia (AML) exhibit increased presence of myeloid-derived suppressor cells (MDSCs) in their peripheral blood, compared to normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b⁺ Gr1⁺ MDSCs in bone marrow and spleen. [Blood] Abstract

Single-Cell RNA Sequencing Highlights Transcription Activity of Autophagy-Related Genes during Hematopoietic Stem Cell Formation in Mouse Embryos

According to the RNA sequencing datasets of five population cells related to hematopoietic stem cell (HSC) formation during mouse embryogenesis (endothelial cells, PTPRC/CD45^– and PTPRC/CD45⁺ pre-HSCs in the E11 aorta-gonad-mesonephros (AGM) region, mature HSCs in E12 and E14 fetal liver), scientists explored the dynamic expression of mouse autophagy-related genes in this course at the single-cell level. [Autophagy] Abstract

CD244 Maintains the Proliferation Ability of Leukemia Initiating Cells through SHP-2/p27kip1 Signaling

Using a MLL-AF9 induced murine acute myeloid leukemia model, researchers showed that leukemogenesis is dramatically delayed upon CD244 deletion, together with remarkably reduced Mac1⁺/c-Kit⁺ leukemia cells. Mechanistically, they reveal that CD244 is associated with c-Kit and p27 except for SHP-2 as previously reported. CD244 cooperates with c-Kit to activate SHP-2 signaling to dephosphorylate p27 and maintain its stability to promote leukemia development. [Haematologica] Abstract

Neomorphic Effects of the Neonatal Anemia (Nan-Eklf) Mutation Contribute to Deficits throughout Development

Investigators showed that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. [Development] Abstract

Young Bone-Marrow Sca-1⁺ Stem Cells Rejuvenate the Aged Heart and Improve Function after Injury through PDGFRβ-Akt Pathway

Scientists reconstituted old mice with young bone marrow (BM) Sca-1⁺ or Sca-1⁻ cells. They found that Sca-1 cells repopulated the recipient BM and homed to the heart. The number of BM-derived cells in the aged myocardium co-expressing PDGFRβ was three times greater in Sca-1⁺ than Sca-1⁻ chimeric mice. Sca-1⁺ chimeras had more active cell proliferation in the infarcted heart and improved ventricular function after myocardial infarction. [Sci Rep] Full Article

The Spleen Microenvironment Influences Disease Transformation in a Mouse Model of KITD^816V-Dependent Myeloproliferative Neoplasm

Investigators characterized mice, which conditionally express the humanized KITD^816V receptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development. They found that KITD^816V mutant animals acquired a myeloproliferative neoplasm similar to polycythemia vera, marked by a massive increase in red blood cells and severe splenomegaly caused by excessive extramedullary erythropoiesis. [Sci Rep] Full Article

CLINICAL RESEARCH

Outcomes of UCB Transplantation Are Comparable in FLT3⁺ AML: Results of CIBMTR, Eurocord and EBMT Collaborative Analysis

The authors found that compared with sibling hematopoietic cell transplantation (HCT), relapse risks were similar after umbilical cord blood (UCB) and unrelated donors (URD). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT but not vs URD. All three cohorts had statistically not significant three-year leukemia-free survival: 39% after UCB, 43% after sibling, and 50% after URD. [Leukemia] Abstract

IFN-β Induces Greater Antiproliferative and Proapoptotic Effects and Increased p53 Signaling Compared with IFN-α in PBMCs of Adult T-Cell Leukemia/Lymphoma Patients

Researchers performed the first direct comparison between the response to interferon alpha (IFN-α) and IFN-β in ex vivo adult T-cell leukemia/lymphoma (ATLL) patient PBMCs. They analyzed samples obtained between 2001 and 2007 from 9 men and 13 women aged 21–78 years, diagnosed as HIV negative and definite ATLL with serology, inverted PCR and/or flow cytometry, at the ‘Hospital Universitário Professor Edgar Santos’ in Salvador, Bahia, Brazil. [Blood Cancer J] Full Article

Lymphocyte Expansion after Unrelated Cord Blood Allogeneic Stem Cell Transplantation in Adults

Large granular lymphocytes (LGL) expansions have been reported after bone marrow or peripheral blood, but not after unrelated cord blood (UCB) allogeneic hematopoietic stem cell transplantation (allo-HSCT), associated with indolent clinical courses and favorable outcomes. Scientists considered 85 recipients of UCB allo-HSCT to more broadly define the impact of lymphocytosis, not limited to LGL. [Bone Marrow Transplant] Abstract

Wanted DEAD/H or Alive: Helicases Winding Up in Cancers

The authors summarize recent findings on the roles of RNA helicases in various cancers, which are broadly classified into adult solid tumors, childhood solid tumors, leukemia, and cancer stem cells. The potential small molecule inhibitors of helicases and their therapeutic value are also discussed. In addition, analyzing next-generation sequencing data obtained from public portals and reviewing existing literature, they provide new insights on the potential of DEAD/H-box helicases to act as pharmacological drug targets in cancers. [J Natl Cancer Inst] Abstract

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

Celgene Receives Positive CHMP Opinion to Expand REVLIMID^® (Lenalidomide) Indication as Monotherapy for the Maintenance Treatment of Patients with Newly Diagnosed Multiple Myeloma (MM) after Autologous Stem Cell Transplantation

Celgene International Sàrl announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for the use of REVLIMID^® as monotherapy for the maintenance treatment of adult patients with newly diagnosed MM who have undergone autologous stem cell transplantation. [Celgene International Sàrl] Press Release

Stephen Gottschalk, M.D., Has Been Named Chair of the Department of Bone Marrow Transplantation and Cellular Therapy at St. Jude Children’s Research Hospital

Stephen Gottschalk, M.D., has been named chair of the Department of Bone Marrow Transplantation and Cellular Therapy at St. Jude Children’s Research Hospital in Memphis, Tennessee. In his new position, Gottschalk will be responsible for management of the department’s clinical, research and educational activities. [St. Jude Children’s Research Hospital] Press Release

AllCells, LLC Opens Quincy, MA Clinical Collection Facility

AllCells, LLC announced the expansion of its clinical division, LeukoLab, with the opening of a second collection facility. The clinic has started screening, qualifying, and accepting donors for fresh whole blood collections. [AllCells, LLC] Press Release

Proposed U.S. Biotech Rules Raise Industry Hopes and Anxieties

Makers of genetically engineered products have long been on the lookout for changes in U.S. regulations. The system that divvies up the safety review of these products between the Food and Drug Administration, Environmental Protection Agency, and U.S. Department of Agriculture is in the middle of a years-long overhaul, in part to accommodate modern gene-editing technologies such as CRISPR. And a set of new proposals released last week offers hints about what those agencies still hope to change. [ScienceInsider] Editorial

Trump Agenda Threatens US Legacy of Science Diplomacy

A newly minted leader with no experience governing at home or establishing policy abroad now oversees the United States’ vast diplomatic enterprise. US President Donald Trump has a deep bench of scientific and technical expertise to tap across multiple government agencies — but it is not clear that he will use it. [Nature News] Editorial

NEW Translational Opportunities in Stem Cell Research
February 27-March 1, 2017
Basel, Switzerland

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

NEW 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)

Scientist – Regulatory Support (Cook MyoSite, Inc.)

Scientist – Regulatory Affairs (Cook MyoSite, Inc.)

Research Group Leader – Leukemia Research (Department of Biomedicine, University Hospital Basel)

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

Tenure Track Faculty – Stem Cells and Regenerative Medicine (University of Notre Dame)

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

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

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)

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.