Hematopoiesis News Volume 10.49 | Dec 17 2019

TOP STORY

Targeting REGNASE-1 Programs Long-Lived Effector T Cells for Cancer Therapy

Investigators used an in vivo pooled CRISPR–Cas9 mutagenesis screening approach to demonstrate that, by targeting REGNASE-1, CD8⁺ T cells were reprogrammed to long-lived effector cells with extensive accumulation, better persistence and robust effector function in tumors. REGNASE-1-deficient CD8⁺ T cells showed markedly improved therapeutic efficacy against mouse models of melanoma and leukemia. [Nature] Abstract | Press Release

(Ranked by impact factor of the journal)

HBO1 Is Required for the Maintenance of Leukemia Stem Cells

To specifically identify novel dependencies in leukemia stem cells (LSCs), researchers screened a bespoke library of small hairpin RNAs that targeted chromatin regulators in a unique ex vivo mouse model of LSCs. They identified the MYST acetyltransferase HBO1 and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. [Nature] Abstract

Rap1 Regulates Hematopoietic Stem Cell Survival and Affects Oncogenesis and Response to Chemotherapy

Using Rap1 null mice, the authors provided the genetic evidence that mammalian Rap1 played a major role in hematopoietic stem cell survival, oncogenesis and response to chemotherapy. Strikingly, this function of RAP1 was independent of its association with the telomere or with its known partner TRF2. [Nat Commun] Full Article

Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

The authors discovered that mutant p53 confered a competitive advantage to hematopoietic stem and progenitor cells (HSPCs) following transplantation and promotef HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacted with EZH2 and enhanced its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. [Nat Commun] Full Article

Inducible Forward Programming of Human Pluripotent Stem Cells to Hemato-Endothelial Progenitor Cells with Hematopoietic Progenitor Potential

Scientists unraveled the function of key transcriptional regulators SCL, LMO2, GATA2, and ETV2 on early hemato-endothelial specification and established a fully inducible and stepwise hemato-endothelial forward programming system based on SLGE-regulated overexpression. [Stem Cell Reports] Full Article

MEK Inhibition Enhances the Response to Tyrosine Kinase Inhibitors in Acute Myeloid Leukemia

The authors used phosphoproteomics to identify differentially-phosphorylated proteins in patients with acute myeloid leukemia and tyronise kinase inhibitors resistance. They then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. [Sci Rep] Full Article

The Role of Phosphorylation of MLF2 at Serine 24 in BCR-ABL Leukemogenesis

Researchers demonstrated that myeloid leukemia factor (MLF)2 may play an oncogenic role in chronic myelogenous leukemia (CML). The expression level of MLF2 was related to the proliferation, colony-formation ability, and sensitivity to imatinib in K562 cells. Moreover, phosphorylation at serine 24, detected through Phos-tag sodium dodecyl sulfate-polyacrylamide gel electrophoresis, was required to maintain the activity of MLF2 in CML. [Cancer Gene Ther] Abstract

CLINICAL RESEARCH

Haploidentical Transplantation Might Have Superior Graft-Versus-Leukemia Effect Than HLA-Matched Sibling Transplantation for High-Risk Acute Myeloid Leukemia in First Complete Remission: A Prospective Multicenter Cohort Study

189 patients with high-risk acute myeloid leukemia (H-AML) in complete remission 1 were enrolled in this multicentre prospective cohort study. Patients were assigned to groups transplanted with a haploidentical donor or matched sibling donor (MSD) based on donor availability. [Leukemia] Abstract

Early Posttransplant Spirometry Is Associated with the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplant

Pre-transplant and day +80 spirometric parameters were analyzed as continuous variables and included in a multivariable model with other factors such as donor source, graft source, conditioning regimen, use of total body irradiation and immunoglobulin levels. Pre-transplant forced expiratory flow (FEF(_25-75, day +80 forced expiratory volume in one second and day +80 FEF_25-27 had the strongest association with increased risk of bronchiolitis obliterans syndrome. [Biol Blood Marrow Transplant] Abstract

Possible Role of Highly Activated Mucosal NK Cells Against Viral Respiratory Infections in Children Undergoing Haematopoietic Stem Cell Transplantation

Investigators determined T and NK cell numbers together with NK activation status in nasopharyngeal aspirates in hematopoietic stem cell transplantation (HSCT) recipients and healthy controls using multiparametric flow cytometry. They also determined by PCR the presence of 16 respiratory viruses. Samples were collected pre-HSCT, at day 0, +10, +20 and +30 after HSCT. [Sci Rep] Full Article

Optimizing Chimeric Antigen Receptor T-Cell Therapy for Adults with Acute Lymphoblastic Leukemia

Adults with chemotherapy refractory B-cell acute lymphoblastic leukemia received CTL019 in 1 of 2 trials. Patients received lymphodepletion followed by CTL019 as either a one-time infusion or fractionated infusions split over three days, which allowed for day two and day three doses to be held for early CRS. Total planned CTL019 dose varied with adaptive protocol modifications in response to efficacy and CRS toxicity. [Int J Clin Oncol] Abstract

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The Role of Allogeneic Stem Cell Transplantation in the Management of Acute Myeloid Leukaemia: A Triumph of Hope and Experience

The accumulated experience of allografting in acute myeloid leukemia over the last four decades has provided critical insights into both the contribution of the conditioning regimen and the graft-versus-leukemia effect to the curative potential of the most common form of immunotherapy utilised in standard clinical practice. [Br J Haematol] Abstract

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Kite and Kiniksa Pharmaceuticals Announce Clinical Collaboration Evaluating Investigational Combination of Yescarta^® and Mavrilimumab in Relapsed or Refractory Large B-Cell Lymphoma

Kite, a Gilead Company, and Kiniksa Pharmaceuticals, Ltd. announced that the companies have entered into a clinical collaboration to conduct a Phase II, multicenter study of mavrilimumab, an investigational fully human monoclonal antibody that targets granulocyte macrophage colony stimulating factor receptor alph, in combination with Yescarta^® in patients with relapsed or refractory large B-cell lymphoma. [Kiniksa Pharmaceuticals, Ltd.] Press Release

BeiGene Announces Results of Phase III ASPEN Trial of Zanubrutinib Compared to Ibrutinib for the Treatment of Patients with Waldenström’s Macroglobulinemia

BeiGene, Ltd. announced results from the Phase III ASPEN trial comparing its BTK inhibitor BRUKINSA™ to ibrutinib for the treatment of Waldenström’s macroglobulinemia. [BeiGene, Ltd.] Press Release

Cellectar Announces Data From 20 Patients Receiving a Single 25mCi/M2 Bolus Dose of CLR 131 in the Phase II CLOVER-1 Study

Cellectar Biosciences, Inc. announced summary data from 20 patients receiving a single dose of CLR 131 in its Phase II CLOVER-1 trial in select relapsed/refractory B-cell malignancies. [Cellectar Biosciences, Inc.] Press Release

CHMP Issues Positive Opinion Recommending DARZALEX^® (Daratumumab) in Combination with Bortezomib, Thalidomide and Dexamethasone in Frontline Multiple Myeloma

Genmab A/S announce that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has issued a positive opinion recommending broadening the existing marketing authorization for DARZALEX^® in the European Union. The recommendation is for the use of DARZALEX in in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant. [Genmab A/S] Press Release

Spending Bill Boosts US Science Budgets, Unlocks Gun Research

For the 2020 fiscal year, most US research agencies will receive a funding increase, according to details of a spending bill released by Congress. A total of $2.8 billion of the NIH budget, a boost of $330 million over this year, will be earmarked for Alzheimer’s research, with another $12.5 million for firearm injury and mortality protection research. [The Scientist] Editorial

The Top Retractions of 2019

Another year, another 1,433 (and counting) retractions. The tenth year of Retraction Watch’s existence included-as is often the case-a new record, some impressive numbers, and some bizarre stories. But it also included some exemplary behavior. [The Scientist] Editorial

NIH Considering New Recommendations on Sexual Harassment Policies

Recommendations put forth by the Working Group on Changing the Culture to End Sexual Harassment include requiring NIH-funded institutions to notify the agency within two weeks when a grant recipient is found guilty of sexual misconduct, barring confirmed harassers from serving on NIH advisory councils, and mandating that grant applicants report sexual harassment findings against them. [The Scientist] Editorial

NEW Lorne Cancer Conference
February 13-15, 2020
Lorne, Australia

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NEW Faculty Position – Cancer Epidemiology (MD Anderson Cancer Center)

Scientist – Hematopoietic Stem and Progenitor Cell Biology (STEMCELL Technologies Inc.)

Research Fellow – Hematology & Blood Disorders (New York Blood Center)

Postdoctoral Position – Oncogenic Events in Acute Lymphoblastic Leuemia (KU Leuven)

Department Director – Hematopathology (University of Vermont)

Postdoctoral Fellowships – Cancer Research (Harvard Medical School)

Postdoctoral Fellowship – Leukemia (Uniformed Services University of the Health Sciences)

Postdoctoral Fellow – Erythropoiesis (Mount Sinai School of Medicine)

Assistant/Associate Professor – Hematology & Oncology (UC Davis School of Medicine)

Associate/Professor – Hematology & Oncology (UC Davis School of Medicine)

PhD Project – Physical Biology of Blood Stem Cells (University of York)

Postdoctoral Fellowship – Leukemia Pathogenesis (BC Cancer)

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