Hematopoiesis News Volume 10.18 | May 14 2019

TOP STORY

Rational Targeting of Cooperating Layers of the Epigenome Yields Enhanced Therapeutic Efficacy against AML

Mechanistically, combination therapy increased enhancer-promoter looping and chromatin-activating marks at the GATA2 locus. CRISPRi of the LSD1-bound enhancer in patient-derived TET2mut AML was associated with dampening of therapeutic GATA2 induction. TET2 knockdown in human HSPCs induced loss of enhancer 5 hydroxymethylation and facilitated LSD1-mediated enhancer inactivation. [Cancer Discov] Abstract

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A Gain-of-Function p53 Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor Foxh1

Scientists identified a gain-of-function p53 mutation that accelerated complex karyotype-acute myeloid leukemia initiation beyond p53 loss and was required for disease maintenance. The p53R172H mutation exhibited a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that was present in hematopoietic stem and progenitor cells even prior to their transformation. [Cancer Discov] Abstract | Full Article

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models

Investigators report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolved from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status was generated via adaptive super-enhancer remodeling that reprogrammed transcription and offered opportunities for overcoming ABT-199 resistance. [Cancer Cell] Abstract | Graphical Abstract

Metabolic Reprogramming toward Oxidative Phosphorylation Identifies a Therapeutic Target for Mantle Cell Lymphoma

Researchers showed that metabolic reprogramming toward oxidative phosphorylation and glutaminolysis was associated with therapeutic resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma, a B cell lymphoma subtype with poor clinical outcomes. [Sci Transl Med] Abstract | Press Release

The Enhancer RNA ARIEL Activates the Oncogenic Transcriptional Program in T-Cell Acute Lymphoblastic Leukemia

The authors demonstrated that ARID5B inducing enhancer associated long non-coding RNA (ARIEL) was specifically activated in TAL1-positive T-cell acute lymphoblastic leukemia cases, and its expression was associated with ARID5B enhancer activity. ARIEL recruited mediator proteins to the ARID5B enhancer, promoted enhancer-promoter interactions, and activated the expression of ARID5B, thereby positively regulating the TAL1-induced transcriptional program and the MYC oncogene. [Blood] Abstract

Hepatic Leukemia Factor Is a Novel Leukemic Stem Cell Regulator in DNMT3A, NPM1, and FLT3-ITD Triple-Mutated AML

Loss of hepatic leukemia factor (HLF)3 via CRISPR/Cas9 significantly reduced the CD34⁺GPR56⁺ leukemia stem cell compartment of primary human triple-mutated acute myeloid leukemia (AML) cells in serial xenotransplantation assays. HLF knockout cells were more actively cycling when freshly harvested from mice, but rapidly exhausted when re-introduced in culture. [Blood] Abstract

Differentiated Fibrocytes Assume a Functional Mesenchymal Phenotype with Regenerative Potential

Using proteomic, bioenergetic, and bioengineering techniques, scientists conducted deep phenotypic characterization of differentiating and mature fibrocytes. Differentiation was associated with metabolic reprogramming that favored oxidative phosphorylation. [Sci Adv] Full Article | Press Release

Hlf Marks the Developmental Pathway for Hematopoietic Stem Cells but Not for Erythro-Myeloid Progenitors

Researchers showed that hepatic leukemia factor (Hlf) expression specifically marked a developmental continuum between HSC precursors and HSCs. Using the Hlf-tdTomato reporter mouse, they found that Hlf was expressed in intra-aortic hematopoietic clusters and fetal liver HSCs. In contrast, erythro-myeloid progenitors and yolk sac hematopoietic clusters before embryonic day 9.5 did not express Hlf. [J Exp Med] Abstract

The Lifespan Quantitative Trait Locus Gene Securin Controls Hematopoietic Progenitor Cell Function

The authors identified a region spanning 12.5 cM on the proximal part of chromosome 11 linked to both the percentage of dysfunctional hematopoietic stem and progenitor cells as well as regulation of lifespan. They demonstrated that this region determined the sensitivity of hematopoietic stem and progenitor cells to hydroxyurea. [Haematologica] Full Article

CD27, CD201, FLT3, CD48, and CD150 Cell Surface Staining Identifies Long-Term Mouse Hematopoietic Stem Cells in Immunodeficient Non-Obese Diabetic Severe Combined Immune Deficient Derived Strains

Scientists demonstrated that HSCs were enriched within the linage-negative C-KIT⁺ CD27⁺ CD201⁺ FLT3^– CD48^– CD150⁺ population in serial dilution long-term competitive transplantation assays. They observed that CD48 expression was up-regulated in Lin^– KIT⁺ progenitors from NOD.CB17-prkdcscid/Sz and NOD.CB17-prkdcscid il2rgtm1Wj1/Sz strains, which otherwise had very few cells expressing the CD48 ligand CD244. [Haematologica] Full Article

CLINICAL RESEARCH

Allogeneic Hematopoietic Cell Transplantation Compared to Chemotherapy Consolidation in Older Acute Myeloid Leukemia (AML) Patients 60-75 Years in First Complete Remission (CR1): An Alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR Study

Investigators compared the outcomes for older AML patients receiving allogeneic hematopoietic cell transplantation with those treated on prospective National Clinical Trials Network induction and nontransplantation chemotherapy consolidation trials. [Leukemia] Abstract

The Mutational Burden of Therapy-Related Myeloid Neoplasms Is Similar to Primary Myelodysplastic Syndrome but Has a Distinctive Distribution

Scientists compared the clinical and mutational characteristics of therapy-related myeloid neoplasms (T-MN) and primary myelodysplastic syndrome (P-MDS) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients, the pattern was distinct. TP53 mutations were more frequent in T-MN, while spliceosomal complex mutations were more common in P-MDS [Leukemia] Abstract

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Long Non-Coding RNA: Classification, Biogenesis and Functions in Blood Cells

The key molecular functions of long non-coding RNAs (lncRNAs) in hematopoiesis are still unclear, particularly, their functional role during megakaryocyte development from HSCs is largely unexplored. The authors summarize the current status of knowledge on lncRNAs classification, biogenesis and its role in blood cells. [Mol Immunol] Abstract

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

uniQure Announces Updated Clinical Data from Phase IIb Study of AMT-061 in Patients with Hemophilia B

uniQure N.V. announced updated clinical data in patients treated in the company’s ongoing Phase IIb study of AMT-061, an investigational AAV5-based gene therapy containing a patent-protected FIX-Padua variant, for the treatment of patients with severe and moderately severe hemophilia B. [Press release from uniQure N.V. discussing research presented at the Hemostasis & Thrombosis Research Society (HTRS) 2019 Scientific Symposium, New Orleans] Press Release

Forty Seven Inc. and Acerta Enter Collaboration to Evaluate Novel Immuno-Oncology Triple Combination in Diffuse Large B-Cell Lymphoma

Forty Seven Inc. announced a collaboration with Acerta Pharma. Under the terms of the collaboration, Acerta will sponsor a clinical trial evaluating Forty Seven’s CD47 antibody 5F9 in combination with rituximab plus Acerta’s CALQUENCE^®, in patients with diffuse large B-cell lymphoma, an aggressive form of non-Hodgkin’s lymphoma. [Forty Seven Inc.] Press Release

ExCellThera Enters into a Manufacturing and Collaboration Agreement with New York Blood Center

ExCellThera Inc. announced that it has entered into a manufacturing and collaboration agreement with Comprehensive Cell Solutions, a division of New York Blood Center for the clinical grade production of ExCellThera’s lead cell therapy product, ECT-001. [ExCellThera Inc.] Press Release

Onconova Therapeutics Announces License Agreement with HanX Biopharmaceuticals to Develop and Commercialize Rigosertib in Greater China

Onconova Therapeutics, Inc. announced that it has entered into a license agreement for the Greater China territory with HanX Biopharmaceuticals, Inc., to develop and commercialize rigosertib, a novel and targeted anti-cancer compound currently in a Phase III study for the treatment of higher-risk myelodysplastic syndromes. [Onconova Therapeutics, Inc.] Press Release

City of Hope Opens First Multiple Myeloma Autologous CAR T Cell Therapy Trial Targeting CS1 Protein on Cancer Cells

City of Hope is now enrolling patients with multiple myeloma whose disease has relapsed, or is treatment-resistant, for a first-of-its kind chimeric antigen receptor (CAR) T cell therapy trial. The study, which is a City of Hope Alpha Stem Cell Clinic trial, will enroll multiple myeloma patients who have already used three treatment options but whose disease has returned or has not responded to treatment. [City of Hope] Press Release

Poseida Therapeutics Receives US FDA Orphan Drug Designation for P-BCMA-101 for the Treatment of Multiple Myeloma

Poseida Therapeutics Inc. announced the FDA has granted orphan drug designation to P-BCMA-101 for the treatment of relapsed and/or refractory multiple myeloma. P-BCMA-101 is an autologous CAR-T therapy developed using Poseida’s piggyBac^® platform technology. [Poseida Therapeutics Inc.] Press Release

Cellectar Receives FDA Fast Track Designation for CLR 131 in Relapsed or Refractory Multiple Myeloma

Cellectar Biosciences, Inc. announced that the FDA has granted Fast Track Designation for CLR 131 in fourth line or later relapse/refractory multiple myeloma. CLR 131 is the company’s small-molecule radiotherapeutic phospholipid drug conjugate designed to deliver cytotoxic radiation directly and selectively to cancer cells and cancer stem cells. [Cellectar Biosciences, Inc.] Press Release

Precision for Medicine to Provide Real-Time Laboratory Testing Services in Unique Lymphoma Patient Stratification Study

Precision for Medicine announced that it will provide its state-of-the-art laboratory services to perform drug assessment as part of a new personalized clinical trial designed to identify the most effective therapies for individual lymphoma patients at The University of Texas MD Anderson Cancer Center. [Precision Medicine Group (PR Newswire Association LLC.)] Press Release

NIH Fears Good-Government Bill Would Hamper Peer Review

The much-admired system to review grant proposals at the National Institutes of Health (NIH) in Bethesda, Maryland, has become the latest flashpoint in a long-running battle between Congress and the executive branch over how the US government manages advisory bodies. NIH’s parent body, the Department of Health and Human Services in Washington, DC, opposes legislation moving rapidly through Congress that is aimed at making those committees more transparent. [ScienceInsider] Editorial

Artificial Intelligence Is Selecting Grant Reviewers in China

China’s largest funder of basic science is piloting an artificial intelligence (AI) tool that selects researchers to review grant applications, in an attempt to make the process more efficient, faster and fairer. Some researchers say the approach by the National Natural Science Foundation of China is world-leading, but others are sceptical about whether AI can improve the process. [Nature News] Editorial

Europe’s Premier Research Funder Appoints New President

Nanobiologist Mauro Ferrari will become president of the European Research Council, the European Union’s premier funder of basic research. Ferrari’s appointment comes as the agency faces challenges to its budget, which cannot currently cover all of the grants that evaluators deem fundable. [Nature News] Editorial

NEW 8^th InterAmerican Oncology Conference
October 17-18, 2019
Buenos Aires, Argentina

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

NEW 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)

Postdoctoral Researcher – Stem Cells & Erythropoiesis in MDS (Karolinska Institutet)

Tenure Track Senior Investigator – Malignant Hematology (Northwestern University Feinberg School of Medicine)

Postdoctoral Fellows – Hematological Malignancies & Cancer Immunology (Fox Chase Cancer Center)

Postdoctoral Fellowship – Myeloma Research (University of Calgary)

Postdoctoral Position – Transcriptional Regulation in Leukemia (VIB KU Leuven)

Postdoctoral Fellowship – Hematopoiesis, Leukemia & Bone Marrow Failure Syndromes (The University of Texas Southwestern)

Associate Scientist – Immuno-Oncology (HMH Center for Discovery & Innovation)

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