Hematopoiesis News Volume 10.27 | Jul 16 2019

TOP STORY

Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging

Researchers showed that the bone marrow (BM) microenvironment promoted myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decreased near bone but expanded further from bone. Increased BM noradrenergic innervation promoted β2-adrenergic-receptor-interleukin-6-dependent megakaryopoiesis. [Cell Stem Cell] Full Article | Graphical Abstract

(Ranked by impact factor of the journal)

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome

Scientists identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine transient abnormal myelopoiesis model, they tested loss-of-function of 22 recurrently mutated myeloid leukemia in Down syndrome (ML-DS) genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS. [Cancer Cell] Abstract | Press Release | Graphical Abstract

A Variant Erythroferrone Disrupts Iron Homeostasis in SF3B1-Mutated Myelodysplastic Syndrome

The authors identified an alternative erythroid hormone erythroferrone (ERFE) transcript in patients with myelodysplastic syndromes with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. [Sci Transl Med] Abstract

Oxidative Stress as Candidate Therapeutic Target to Overcome Microenvironmental Protection of CLL

Investigators compared the transcriptomes of primary chronic lymphocytic leukemia (CLL) cells cocultured or not with protective bone marrow stromal cells and found that oxidative phosphorylation, mitochondrial function, and hypoxic signaling underwent most significant dysregulation in non-protected CLL cells, with the changes peaking at six-eight hours, directly before induction of apoptosis. [Leukemia] Abstract

Genetic Characterization of ABT-199 Sensitivity in Human AML

Researchers screened a library of clinical drugs on a cohort of primary human acute myeloid leukemia (AML) specimens and identified the BCL2 inhibitor ABT-199 as a selective agent against mutated NPM1 gene AML. Mutational analysis of ABT-199-sensitive and -resistant specimens identified mutations in NPM1, RAD21, and IDH1/IDH2 as predictors of ABT-199 sensitivity. [Leukemia] Abstract

HIF-1α Is Overexpressed in Leukemic Cells from TP53-Disrupted Patients and Is a Promising Therapeutic Target in Chronic Lymphocytic Leukemia

Scientists demonstrated that chronic lymphocytic leukemia cells from TP53-disrupted (TP53dis) patients had constitutively higher expression levels of the α-subunit of hypoxia-inducible factor 1 (HIF-1α) and increased HIF-1 transcriptional activity, compared to the wild type counterpart. In the TP53dis subset, HIF-1α upregulation was due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein. [Haematologica] Abstract

Mesenchymal Stromal Cells Confer Chemoresistance to Myeloid Leukemia Blasts through Side Population Functionality and ABC Transporter Activation

The authors demonstrated that contact with mesenchymal stromal cells promoted a better survival of blasts in culture in the presence of anthracycline through the activation of ABC transporters. Stroma-dependent ABC transporter activation led to the induction of a side population phenotype in a subpopulation of primary leukemia blasts through Alpha4 engagement. [Haematologica] Abstract

Synthetic Lethality of Combined AT-101 with Idarubicin in Acute Myeloid Leukemia via Blockade of DNA Repair and Activation of Intrinsic Apoptotic Pathway

Investigators report that combination of Bcl-2 inhibitor AT-101 and chemotherapeutic drug idarubicin resulted in synergistic lethality in CD34⁺CD38^– leukemia stem-like cells sorted from KG-1α and kasumi-1 acute myeloid leukemia (AML) cell lines and primary CD34⁺ AML cells in vitro while sparing the normal counterparts. [Cancer Lett] Abstract

Oncogenic KIT Mutations Induce STAT3-Dependent Autophagy to Support Cell Proliferation in Acute Myeloid Leukemia

Invalidation of the key autophagy protein Atg12 strongly reduced tumor burden and improved survival of immunocompromised NSG mice engrafted with KIT^D816V TF-1 cells. Downstream of KIT^D816V, STAT3, but not AKT or ERK pathways, was identified as a major regulator of autophagy. [Oncogenesis] Full Article

CLINICAL RESEARCH

Treatment with Humanized Selective CD19CAR-T Cells Shows Efficacy in Highly Treated B-ALL Patients Who Have Relapsed after Receiving Murine-Based CD19CAR-T Therapies

A CD19 humanized selective chimeric antigen receptor (CAR) was designed, which incorporated a short selective domain between the humanized heavy chain and light chain. The CAR was examined for its property, and then trialed in five highly treated B-ALL patients. [Clin Cancer Res] Abstract

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Gene Therapy of Hematological Disorders: Current Challenges

The author discusses tools used in gene therapy for hematological disorders, choices of target cells, and delivery vehicles with emphasis on current hurdles and attempts to solve them, and presents examples of successful clinical trials to give a glimpse of current progress. [Gene Ther] Abstract

Emerging Agents and Regimens for Treatment of Relapsed and Refractory Acute Myeloid Leukemia

With the deepening of research, new chemotherapy regimens, new small molecule inhibitors, and immunotherapy have been increasingly applied to clinical trials, providing more possibilities for the treatment of relapsed and refractory acute myeloid leukemia. [Cancer Gene Ther] Abstract

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

Advancing Leading Edge Cancer Research in a $4.5 Million Collaboration

A three-way $4.5 million collaboration launched between The Leukemia & Lymphoma Society, The Mark Foundation for Cancer Research, and The Paul G. Allen Frontiers Group will drive an innovative new funding initiative to propel cutting-edge research to unleash the next wave of novel cancer therapies. [The Leukemia & Lymphoma Society] Press Release

Aptose Doses First CLL Patient in Phase I Study of CG-806 and Doses Third Cohort in Phase I Study of APTO-253

Aptose Biosciences Inc. announced that dosing of CG-806, the company’s highly potent, first-in-class pan-FLT3/pan-BTK inhibitor, has commenced its Phase Ia/b dose-escalation study in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma or non-Hodgkin lymphomas who have failed or are intolerant to standard therapies. [Aptose Biosciences Inc.] Press Release

Ascentage Pharma Announces First Patient Dosed in Phase I Clinical Trial of APG-2575 in China as the First China-Made Bcl-2 Inhibitor

Ascentage Pharma announced that the company recently dosed the first patient successfully in a Phase I clinical trial of APG-2575, a novel Bcl-2 selective inhibitor, for the treatment of hematologic malignancies in China. [Ascentage Pharma] Press Release

Teneobio Doses First Patient in Phase I Study of TNB-383B for the Treatment of Patients with Multiple Myeloma

Teneobio, Inc. announced that the first patient has been dosed with TNB-383B in a Phase I clinical study to evaluate the safety and tolerability of its differentiated anti-BCMAxCD3, a bispecific antibody that redirects T-cells to kill multiple myeloma cells with minimal cytokine release. [Teneobio, Inc.] Press Release

Nordic Nanovector Completes Patient Enrolment into Phase I Trial of Betalutin^® in Diffuse Large B-Cell Lymphoma (DLBCL)

Nordic Nanovector ASA announced that the final patient has been enrolled in the LYMRIT 37-05 clinical trial of Betalutin^® in patients with relapsed/refractory DLBCL not eligible for stem cell transplantation. [Nordic Nanovector ASA] Press Release

Syndax Pharmaceuticals Announces FDA Clearance of IND Application for Targeted Menin Inhibitor SNDX-5613 for Relapsed/Refractory Acute Leukemias

Syndax Pharmaceuticals, Inc. announced that the FDA has cleared the company’s Investigational New Drug (IND) application to begin a Phase I/II trial for SNDX-5613, a targeted Menin inhibitor, in patients with relapsed/refractory acute leukemias. [Syndax Pharmaceuticals, Inc.] Press Release

Omeros Announces Agreement with FDA on Primary Endpoint for Narsoplimab BLA in Stem Cell Transplant-Associated TMA

Omeros Corporation announced agreement with the FDA on the response-based primary endpoint for its pivotal trial to support the biologics license application (BLA) for narsoplimab to treat hematopoietic stem cell transplant-associated thrombotic microangiopathy (TMA). [Omeros Corporation] Press Release

Janssen Submits Application to US FDA Seeking Approval of New DARZALEX^® Subcutaneous Formulation

The Janssen Pharmaceutical Companies of Johnson & Johnson announced the submission of a Biologics License Application (BLA) to the FDA seeking approval of a new subcutaneous formulation of DARZALEX^®, an intravenous treatment approved for certain patients with multiple myeloma. [Janssen Global Services, LLC] Press Release

Moleculin Files for New Patents for Annamycin after Receiving FDA Approval of Fast Track Designation

Moleculin Biotech, Inc. announced it has filed new patents covering the production and reconstitution of annamycin, which is currently in two clinical trials for the treatment of relapsed or refractory acute myeloid leukemia. [Moleculin Biotech, Inc.] Press Release

University of California Loses Access to New Journal Articles Published by Elsevier after Research Access Fight

Researchers in the University of California system lost subscription access to the major publisher Elsevier, the result of a closely watched fight between the two parties over how academic research should get read and paid for. [STAT News] Editorial

US Senators Call for International Guidelines for Germline Editing

Senators Dianne Feinstein, Marco Rubio, and Jack Reed introduced a resolution calling for global collaboration in developing guidelines for the use of gene editing technologies in the context of reproduction. [The Scientist] Editorial

NEW Keystone Symposia: Cancer Stem Cells: Advances in Biology & Clinical Translation
October 13-17, 2019
Hong Kong, China

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

NEW Postdoctoral Position – Advanced Proteomics & Erythropoiesis (Lund University)

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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