Hematopoiesis News Volume 10.23 | Jun 18 2019

TOP STORY

Loss of EZH2 Reprograms BCAA Metabolism to Drive Leukemic Transformation

Researchers showed that EZH2 and NRasG12D mutations cooperatively induced progression of myeloproliferative neoplasms to highly penetrant, transplantable and lethal myeloid leukemias in mice. EZH1, an EZH2 homolog, was indispensable for EZH2-deficient leukemia-initiating cells and constituted an epigenetic vulnerability. [Cancer Discov] Abstract

(Ranked by impact factor of the journal)

Antibody Conditioning Enables MHC-Mismatched Hematopoietic Stem Cell Transplants and Organ Graft Tolerance

Scientists report an antibody-based conditioning protocol with reduced toxicity and enhanced specificity for robust HSC transplantation and engraftment in recipient mice. Host pre-treatment with six monoclonal antibodies targeting CD47, T cells, NK cells, and HSCs followed by donor HSC transplantation enabled stable hematopoietic system reconstitution in recipients with mismatches at half or all major histocompatibility complex (MHC) genes. [Cell Stem Cell] Abstract | Press Release | Graphical Abstract

The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis

The authors found that HVEM deficiency increased B cell competitiveness during pre-germinal center (GC) and GC responses. The immunoglobulin superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. [Immunity] Full Article | Graphical Abstract

Loss of KDM6A Confers Drug Resistance in Acute Myeloid Leukemia

KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. Investigators revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 by reduced H3K27 acetylation at the ENT1 locus. [Leukemia] Full Article

Ephrin/Eph Receptor Interaction Facilitates Macrophage Recognition of Differentiating Human Erythroblasts

Researchers detected a rise in integrin activation on erythroblasts at the stage at which the cells bind which was independent of EPH receptor presence. They showed that specific inhibitory peptides or shRNA depletion of EPHB4 caused a significant reduction in the ability of macrophages to interact with erythroblasts but did not affect integrin activation. [Haematologica] Abstract

Autologous, Gene-Modified Hematopoietic Stem and Progenitor Cells Repopulate the Central Nervous System with Distinct Clonal Variants

Scientists quantified hematopoietic stem and progenitor cell (HSPC) trafficking to 20 tissues including lymph nodes, spleen, liver, gastrointestinal tract, central nervous system (CNS), and reproductive tissues. They observed efficient marking of multiple macrophage subsets, including CNS-associated myeloid cells, suggesting that HSPC-derived macrophages are a viable approach to target gene-modified cells to tissues. [Stem Cell Reports] Full Article

Heart Failure Drug Proscillaridin A Targets MYC Overexpressing Leukemia through Global Loss of Lysine Acetylation

Proscillaridin A anticancer activity was investigated against a panel of human leukemia and solid tumor cell lines with different MYC expression levels, overexpression in vitro systems and leukemia stem cells. RNA-sequencing and differentiation studies were used to characterize transcriptional and phenotypic changes. [J Exp Clin Cancer Res] Full Article

Deferasirox Drives ROS-Mediated Differentiation and Induces Interferon-Stimulated Gene Expression in Human Healthy Hematopoietic Stem/Progenitor Cells and in Leukemia Cells

Deferasirox (DFX), at clinically relevant concentrations, increased the clonogenic capacity of healthy human CD34⁺ hematopoietic stem/progenitor cells to form erythroid colonies. Extension of this analysis to human-derived leukemia cell lines Kasumi-1, K562 and HL60 confirmed DFX capacity to upregulate the expression of specific markers of hematopoietic commitment. [Stem Cell Res Ther] Full Article

CLINICAL RESEARCH

Prognostic Value of the FUT Family in Acute Myeloid Leukemia

From the Cancer Genome Atlas database, a total of 155 acute myeloid leukemia patients with complete clinical characteristics and fucosyltransferase (FUT) 1-11 expression data were included in the study. Patients who received chemotherapy alone showed that high expression levels of FUT3, FUT6, and FUT7 had adverse effects on event-free survival (EFS) and overall survival (OS), whereas high FUT4 expression had favorable effects on EFS and OS. [Cancer Gene Ther] Abstract

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Hematopoietic Progenitor Cells as Integrative Hubs for Adaptation to and Fine-Tuning of Inflammation

Sustained adaptive responses of progenitor cells in the bone marrow can contribute to trained immunity, a non-specific memory of earlier encounters that in turn facilitates the heightened response of these cells, as well as that of their progeny, to future challenges. The authors discuss the mechanisms that govern the adaptation of hematopoietic progenitor cells to inflammation and its sequelae in the pathogenesis of human disease. [Nat Immunol] Abstract

Laying the Foundation for Genomically-Based Risk Assessment in Chronic Myeloid Leukemia

Investigators review publications that reported mutated cancer-associated genes in chronic myeloid leukemia patients at various disease phases. They discuss the frequency and type of such variants at initial diagnosis and at the time of treatment failure and transformation. Current limitations in the evaluation of mutants and recommendations for future reporting are outlined. [Leukemia] Abstract

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

Amgen Announces BLINCYTO^® (Blinatumomab) Five-Year Overall Survival Data

Amgen announced the five-year overall survival analysis from the single-arm, Phase II BLAST study that evaluated BLINCYTO^® in patients with minimal residual disease-positive acute lymphoblastic leukemia [Press release from Amgen Inc. discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

Novartis Continues to Innovate in CML with Long-Term Treatment-Free Remission Results Following Tasigna^® Use and Promising Combination Data with Investigational Compound Asciminib (ABL001)

Long-term follow-up data from the ongoing, pivotal open-label ENESTfreedom and ENESTop trials showed sustained treatment-free remission after stopping frontline and second-line Tasigna therapy in eligible adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. [Press release from Novartis AG discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

Bristol-Myers Squibb Presents Updated Efficacy Data from Phase II Trial of Empliciti (Elotuzumab) plus Pomalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Bristol-Myers Squibb Company announced the presentation of updated data from ELOQUENT-3, the international randomized Phase II study evaluating Empliciti plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in patients with RRMM. [Press release from Bristol-Myers Squibb Company discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

GBT Announces Updated 24-Week Efficacy Data from All Patients Enrolled in Phase III HOPE Study Showing Statistically Significant and Sustained Improvements in Hemoglobin with Voxelotor

Global Blood Therapeutics, Inc. (GBT) announced new results from its Phase III HOPE study of voxelotor in patients ages 12 and older with sickle cell disease. [Press release from Global Blood Therapeutics, Inc. discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

ORYZON Presents Preliminary Dose Finding Results of Phase II Trial with Iadademstat in AML

Oryzon Genomics, S.A. presented preliminary data from part I of the Phase II trial ALICE, which investigates iadademstat in combination with azacitidine in elderly patients with acute myeloid leukemia (AML). [Press release from Oryzon Genomics, S.A. discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

ArQule Announces Clinical Proof-of-Concept Data from Ongoing Phase I Study of Reversible BTK Inhibitor, ARQ 531, in Patients with Relapsed/Refractory Hematologic Malignancies

ArQule, Inc. announced preliminary results from the company’s Phase I dose escalation study for ARQ 531, an orally bioavailable, potent and reversible dual inhibitor of both wild type and C481S-mutant Bruton’s tyrosine kinase (BTK) in patients with relapsed or refractory hematologic malignancies. [Press release from ArQule, Inc. discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

Celyad Presents Clinical Update for CYAD-01

Celyad announced that updated clinical data for the CYAD-01 program in relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome was presented in a poster presentation session. [Press release from Celyad discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

Calquence Significantly Prolonged the Time Patients Lived without Disease Progression in Relapsed or Refractory Chronic Lymphocytic Leukemia

AstraZeneca announced detailed results from the interim analysis of the Phase III ASCEND trial, showing Calquence significantly prolonged the time patients live without disease progression in relapsed or refractory chronic lymphocytic leukemia. [Press release from AstraZeneca discussing research presented at the 24^th Annual Congress of the European Hematology Association (EHA), Amsterdam] Press Release

CASI Pharmaceuticals Acquires Worldwide Rights to Commercialize Anti-CD19 T-Cell Therapy

CASI Pharmaceuticals, Inc. announced the signing of a license agreement for exclusive worldwide license and commercialization rights to an autologous anti-CD19 T-cell therapy product (CNCT19) from Juventas Cell Therapy Ltd. CNCT19 targets CD19, a B-cell surface protein widely expressed during all phases of B-cell development and a validated target for B-cell driven hematological malignancies. [CASI Pharmaceuticals, Inc.] Press Release

Tolero Pharmaceuticals Announces First Patient Dosed with Investigational Agent TP-0903 in Phase I/II Study in Patients with Previously Treated Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Tolero Pharmaceuticals, Inc. announced that the first patient has been dosed in a Phase I/II study evaluating the investigational agent TP-0903, an AXL receptor tyrosine kinase inhibitor, in patients with previously treated chronic lymphocytic leukemia and small lymphocytic lymphoma. [Tolero Pharmaceuticals, Inc.] Press Release

Servier Announces European Commission Decision to Convert Conditional Approval into Standard Marketing Authorization in Patients with Aggressive Non-Hodgkin B-Cell Lymphoma for PIXUVRI^® (Pixantrone)

Servier announced that the European Commission has approved the conversion of the conditional approval of PIXUVRI^® into a standard marketing authorization as a single agent for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphoma. [Servier (Business Wire, Inc.)] Press Release

Daiichi Sankyo’s VANFLYTA^® Receives Approval in Japan for the Treatment of Relapsed/Refractory FLT3-ITD AML

Daiichi Sankyo Company, Limited announced that the Ministry of Health, Labor and Welfare (MHLW) of Japan has approved VANFLYTA^®, an oral FLT3 inhibitor, for the treatment of adult patients with relapsed/refractory FLT3-ITD acute myeloid leukemia (AML), as detected by an MHLW-approved test. [Daiichi Sankyo Company, Limited] Press Release

Kleo Pharmaceuticals Announces a CD38 Targeting Antibody Recruiting Molecule (ARM^™) to Treat Multiple Myeloma as the First Clinical Candidate in Its Partnership with PeptiDream

Kleo Pharmaceuticals, Inc. announced that CD38-ARM, a CD38 targeting antibody recruiting molecule to treat multiple myeloma, will be its first product candidate to move into the clinic with anticipated human studies to commence in 2020. [Kleo Pharmaceuticals, Inc. (PR Newswire Association LLC.)] Press Release

Africa’s Science Academy Leads Push for Ethical Data Use

The African Academy of Sciences has started work on the continent’s first cross-disciplinary guidelines on how to collect, store and share research data and specimens in ways that protect study participants from exploitation and benefit African citizens. [Nature News] Editorial

China Clamps Down on Foreign Use of Chinese Genetic Material and Data

China has announced new regulations for the use of human genetic resources that come from Chinese participants. The rules, announced on June 10, require international scientists using biomaterials from China to have a Chinese collaborator and go into effect on July 1. [The Scientist] Editorial

NEW The 5^th Canadian Cancer Research Conference
November 3-5, 2019
Ottawa, Ontario, Canada

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

NEW Postdoctoral Fellow – Hematopoietic Stem Cell Niche in Leukemia (Erasmus Medical Center)

NEW 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)

Researcher – Clonal Hematopoiesis & Molecular Epidemiology (Uppsala University)

Postdoctoral Scholar – Pediatric Hematology/Oncology (Pennsylvania State University)

Postdoctoral Fellow – Molecular Mechanisms of Myeloma (City of Hope)

Postdoctoral Research Fellow – Translational Gene Therapy & Hematopoietic Stem Cell Research (Fred Hutchinson Cancer Research Center)

Postdoctoral Position – Stem Cell Transplantation Cell Interaction (University of Illinois at Chicago)

Assistant Professor – Lymphoma/Myeloma Research (The University of Texas MD Anderson Cancer Center)

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