Hematopoiesis News Volume 10.28 | Jul 23 2019

TOP STORY

Making Cancer Stem Cells Visible to the Immune System – New Results May Enable Innovative Treatment Concept against Leukemia

Leukemia stem cells protect themselves against the immune defense by suppressing a target molecule for killer cells. This protective mechanism can be tricked with drugs. Scientists from Basel, Tübingen and Heidelberg describe the new therapeutic approaches that can possibly be derived from these results. [Press release from German Cancer Consortium discussing online prepublication in Nature] Press Release | Abstract

(Ranked by impact factor of the journal)

Targeting Cell Membrane HDM2: A Novel Therapeutic Approach for Acute Myeloid Leukemia

The authors showed that membrane human double minute 2 (mHDM2) was exclusively expressed on human and mouse AML blasts, including leukemia stem cell-enriched subpopulations, but not on normal HSCs. Higher mHDM2 levels in AML blasts were associated with leukemia-initiating capacity, quiescence, and chemoresistance. [Leukemia] Abstract

Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation

GMB-475 reduced viability and increased apoptosis in primary chronic myeloid leukemia (CML) CD34⁺ cells, with no effect on healthy CD34⁺ cells at identical concentrations. GMB-475 degraded BCR-ABL1 and reduced cell viability in primary CML stem cells. [Cancer Res] Abstract

Integrin-α3 Is a Functional Marker of Ex Vivo Expanded Human Long-Term Hematopoietic Stem Cells

Researchers identified integrin-α3 (ITGA3) as a marker of cultured human HSCs. They showed that ITGA3 expression was sufficient to separate the primitive EPCR⁺CD90⁺CD133⁺CD34⁺CD45RA⁻ HSC population into two functionally distinct fractions presenting mostly short-term and both short-term and long-term repopulating potential. [Cell Rep] Full Article | Graphical Abstract

Constitutive Activation of the B Cell Receptor Underlies Dysfunctional Signaling in Chronic Lymphocytic Leukemia

Investigators demonstrated that alterations in B cell receptor (BCR) signaling dynamics underlie the progression of B cells toward malignancy. They revealed emergent dynamic features—bimodality, hypersensitivity, and hysteresis—in the BCR signaling pathway of primary chronic lymphocytic leukemia B cells. [Cell Rep] Full Article | Graphical Abstract

Human Cytomegalovirus Enters the Primary CD34⁺ Hematopoietic Progenitor Cells Where It Establishes Latency by Macropinocytosis

The capsid-associated tegument protein pp150 was released from maturing endosomes and migrated to the nucleus, whereas other tegument proteins, including pp71, remained endosome associated in the cytoplasm. The inhibition of macropinocytosis impaired entry, thereby diminishing latency-associated transcription and reducing viral reactivation. [J Virol] Abstract

Novel Strategy for Rapid Functional In Vivo Validation of Oncogenic Drivers in Hematological Malignancies

The authors confirmed that MN1 overexpression in the hematopoietic lineage was sufficient to drive myeloid leukemia. In addition, they showed that T-cell specific activation of MN1 in combination with loss of Pten increased tumor penetrance and stimulated the formation of Lyl1⁺ murine T-cell lymphoblastic leukemias or lymphomas. [Sci Rep] Full Article

LW-213, a Newly Synthesized Flavonoid, Induces G2/M Phase Arrest and Apoptosis in Chronic Myeloid Leukemia

LW-213 treatment degraded the downstream proteins of BCR-ABL1, such as oncoproteins AKT, STAT3/5 in chronic myeloid leukemia (CML) cells, which was blocked by NH₄Cl. In primary CML cells and CD34⁺ stem cells, LW-213 maintained its pro-apoptotic activity. [Acta Pharmacol Sin] Abstract

CLINICAL RESEARCH

Super-Resolution Microscopy Reveals Ultra-Low CD19 Expression on Myeloma Cells That Triggers Elimination by CD19 CAR-T

Researchers applied single molecule-sensitive direct stochastic optical reconstruction microscopy, and demonstrated CD19 expression on a fraction of myeloma cells in 10 out of 14 patients. In contrast, flow cytometry detected CD19 in only two of these ten patients, on a smaller fraction of cells. Treatment with CD19 CAR-T in vitro resulted in elimination of CD19-positive myeloma cells, including those with <100 CD19 molecules per cell. [Nat Commun] Full Article

Sorafenib plus Intensive Chemotherapy Improves Survival in Patients with Newly Diagnosed, FLT3-Internal Tandem Duplication Mutation-Positive Acute Myeloid Leukemia

Scientists investigated whether the addition of sorafenib to intensive induction chemotherapy improved outcomes in patients with FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML). In total, 183 patients who were newly diagnosed with FLT3-ITD-mutated AML between February 2001 and December 2017 were identified. [Cancer] Abstract

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The Genetics of Human Hematopoiesis and Its Disruption in Disease

The authors discuss advances in functionally characterizing common variants associated with blood cell traits and discuss therapeutic insights, such as the discovery of BCL11A as a modulator of fetal hemoglobin expression. Finally, as genetic techniques continue to evolve, they discuss the prospects, challenges, and unanswered questions that lie ahead in this burgeoning field. [EMBO Mol Med] Full Article

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Humanigen Secures Exclusive Worldwide License for the Prevention of GvHD through GM-CSF Neutralization from the University of Zurich

The Humanigen license covers various patent applications filed by University of Zurich which complement and broaden Humanigen’s leadership position in the application of granulocyte macrophage-colony stimulating factor (GM-CSF) and expand Humanigen’s development platform to include improving allogeneic hematopoietic stem cell therapy. [Humanigen, Inc.] Press Release

Actinium Achieves Fifty Percent Enrollment in the Pivotal Phase III SIERRA Trial for Iomab-B

Actinium Pharmaceuticals, Inc. announced that the 75^th patient has been treated in the pivotal Phase III SIERRA trial of Iomab-B, thus achieving 50 percent patient enrollment for the trial. [Actinium Pharmaceuticals, Inc.] Press Release

CTI BioPharma Announces Outcome from End-of-Phase-IIa Meeting with US Food and Drug Administration (FDA) regarding Pacritinib for Treatment of Myelofibrosis

CTI BioPharma Corp. announced the outcome of a Type B, End-of-Phase-IIa meeting with the FDA for the continued development of its investigational myelofibrosis treatment candidate, pacritinib. Following this meeting, CTI plans to evaluate 200 mg of pacritinib administered twice daily in 180 patients with myelofibrosis and severe thrombocytopenia. [CTI BioPharma Corp.] Press Release

MacroGenics Provides Update on Flotetuzumab Program in Acute Myeloid Leukemia

MacroGenics, Inc. announced that it plans to advance the development of flotetuzumab, its investigational bispecific CD123 x CD3 DART^® molecule, in patients with primary refractory acute myeloid leukemia, a difficult-to-treat patient population. [MacroGenics, Inc.] Press Release

Moleculin Announces Annamycin in Acute Myeloid Leukemia in Poland Advances to 3^rd Cohort

Moleculin Biotech, Inc. announced additional positive interim safety and efficacy data from its ongoing open label, single arm Phase I/II study of annamycin in Poland. Three patients were treated at dose level of 150 mg/m² with no drug-related adverse events, including no signs of cardiotoxicity. [Moleculin Biotech, Inc.] Press Release

Ascentage Pharma to Initiate Phase Ib Study of HQP1351 in Tyrosine Kinase Inhibitors-Resistant Chronic Myeloid Leukemia Patients in the US

Ascentage Pharma announced that the company was notified by the FDA on the clearance of the Investigational New Drug application which allows the company to initiate its Phase Ib clinical trial of HQP1351, a novel drug candidate developed by Ascentage Pharma, for the treatment of patients with tyrosine kinase inhibitor-resistant chronic myeloid leukemia in the United States. [Ascentage Pharma (PR Newswire Association LLC.)] Press Release

CStone Receives Approval in China to Initiate Ivosidenib Phase I Bridging Registrational Study for the Treatment of IDH1 Mutant Relapsed or Refractory AML

CStone Pharmaceuticals announced that it has received approval from the China National Medical Products Administration to initiate a Phase I bridging registrational study of ivosidenib for the treatment of relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation. [CStone Pharmaceuticals] Press Release

Akebia Therapeutics Announces Submission of Vadadustat New Drug Application in Japan for Anemia Due to Chronic Kidney Disease by Collaboration Partner, MTPC

Akebia Therapeutics, Inc. announced that Mitsubishi Tanabe Pharma Corporation (MTPC), its development and commercialization collaboration partner in Japan for vadadustat, Akebia’s investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor, has submitted a Japanese New Drug Application to the Ministry of Health, Labor and Welfare in Japan for manufacturing and marketing approval of vadadustat as a treatment for anemia due to chronic kidney disease. [Akebia Therapeutics, Inc.] Press Release

Budget Deal Raises Hopes for US Research Agencies

A new budget deal between the White House and congressional leaders means US research agencies could receive increases on the order of the 4% to 5% that Democrats have already proposed for next year. [ScienceInsider] Editorial

What Boris Johnson’s Leadership Could Mean for Science

Boris Johnson has been selected as the United Kingdom’s new prime minister — and is poised to lead the country out of the European Union (EU). At the forefront of many scientists’ minds are questions about how Johnson’s leadership, including his support for a ‘no deal’ Brexit, will affect research. They fear that British science has much to lose from a messy departure from the EU. [Nature News] Editorial

NEW XVIII International Workshop on CLL (iwCLL) Meeting
September 20-23, 2019
Edinburgh, Scotland

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

NEW Postdoctoral Position – Genome Editing of Hematopoietic Stem Cells (Bar-Ilan University)

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)

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