Hematopoiesis News Volume 4.21 | Jun 4 2013

LABORATORY RESEARCH

Acute Myeloid Leukemia Creates an Arginase-Dependent Immunosuppressive Microenvironment
Researchers investigated the mechanisms by which acute myeloid leukemia (AML) causes pancytopenia and suppresses patients’ immune response. They identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. [Blood] Abstract

Targeting of the MNK-eIF4E Axis in Blast Crisis Chronic Myeloid Leukemia Inhibits Leukemia Stem Cell Function
Researchers showed that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in blast crisis (BC) granulocyte macrophage progenitors (GMPs) but not normal hematopoietic stem cells, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates β-catenin signaling in BC GMPs. [Proc Natl Acad Sci USA] Abstract

Essential, Dose-Dependent Role for the Transcription Factor Gata3 in the Development of IL-5⁺ and IL-13⁺ Type 2 Innate Lymphoid Cells
Whereas the transcription factor GATA binding protein 3 (Gata3) is important for the production of IL-5 and -13 by group 2 innate lymphoid cells (ILC2s) in response to IL-33 or -25 stimulation, it is not known whether Gata3 is required for ILC2 development from hematopoietic stem cells. Investigators showed that chimeric mice generated with Gata3-deficient fetal liver hematopoietic stem cells fail to develop systemically dispersed ILC2s. [Proc Natl Acad Sci USA] Abstract

Mouse Gene Targeting Reveals an Essential Role of mTOR in Hematopoietic Stem Cell Engraftment and Hematopoiesis
Although mTOR has been established as a therapeutic target in hematological malignancies, its physiological role in regulating hematopoiesis remains unclear. The authors showed that conditional gene targeting of mTOR causes bone marrow failure and defects in multi-lineage hematopoiesis including myelopoiesis, erythropoiesis, thrombopoiesis, and lymphopoiesis. [Haematologica] Abstract | Full Article

FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors
Whether signals mediated via growth factor receptors might influence lineage fate in multipotent progenitors is unclear. The authors explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. [Cell Rep]
Abstract | Full Article | Graphical Abstract

H/ACA Small RNA Dysfunctions in Disease Reveal Key Roles for Noncoding RNA Modifications in Hematopoietic Stem Cell Differentiation
Investigators carried out comprehensive profiling of dyskerin-associated H/ACA ribonucleoproteins, revealing remarkable heterogeneity in the expression and function of subsets of H/ACA small RNAs in X-linked dyskeratosis congenita (X-DC) patient cells. Using a mass spectrometry approach, they uncovered single-nucleotide perturbations in dyskerin-guided ribosomal RNA modifications, providing functional readouts of small RNA dysfunction in X-DC. In addition, they identified that, strikingly, the catalytic activity of dyskerin is required for accurate hematopoietic stem cell differentiation. [Cell Rep]
Abstract | Full Article | Graphical Abstract

WNT3A Promotes Hematopoietic or Mesenchymal Differentiation from hESCs Depending on the Time of Exposure
Scientists investigated the role of canonical WNT signaling in mesoderm and hematopoietic development from human embryonic stem cells (hESCs) using a recombinant human protein-based differentiation medium. [Stem Cell Rep] Abstract | Full Article | Graphical Abstract

CLINICAL RESEARCH

Significant Improvement in Survival after Allogeneic Hematopoietic Cell Transplantation during a Period of Significantly Increased Use, Older Recipient Age, and Use of Unrelated Donors
Over the past four decades, allogeneic hematopoietic cell transplantation has evolved as a curative modality for patients with hematologic diseases. Researchers described changes in use, technique, and survival in a population-based cohort. [J Clin Oncol] Abstract | Press Release

Long-Term Survival with Low Toxicity after Allogeneic Transplantation for Acute Myeloid Leukemia and Myelodysplasia Using Non-Myeloablative Conditioning without T Cell Depletion
The toxicity burden and long-term anti-leukemic effect of non-myeloablative (NMA) allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia (AML) and myelodysplasia (MDS) remains undefined. Investigators reported the outcome of 56 patients with AML/MDS transplanted from human leucocyte antigen-matched donors using NMA conditioning without T-cell depletion. [Br J Haematol] Abstract

Combination of Fludarabine, Amsacrine, and Cytarabine followed by Reduced-Intensity Conditioning and Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia
Sequential use of chemotherapy and reduced-intensity conditioning with allogeneic stem cell transplantation has been proposed to improve the treatment outcomes in patients with high-risk acute myeloid leukemia (AML). Researchers present their experience with this procedure in a cohort of 60 AML patients with primary induction failure; early, refractory, or ≥ second relapse; or unfavorable cytogenetics. [Ann Hematol] Abstract

DCPrime’s Phase I/IIa Trial with Dendritic Cancer Vaccine in Acute Myeloid Leukemia Meets All Clinical Endpoints
Cancer vaccine company DCPrime announced the successful completion of its Phase I/IIa study in acute myeloid leukemia. The study establishes the safety and feasibility of vaccination with DCPrime’s lead product DCP-001, and shows clear evidence of a positive, vaccination induced immune response. Remarkably, several patients showed prolonged survival compared to historic expectations. [Business Wire] Press Release

Sosei Announces Establishment of a Regenerative Medicine Fund
Sosei Group announces that at the meeting of the Board of Directors, it resolved to invest in the regenerative medicine fund run by the newly-established subsidiary Sosei Corporate Venture Capital (Sosei CVC). Sosei Group will pursue a new venture through Sosei CVC. [Sosei Group Corporation] Press Release

GSK and Genmab Announce Positive Top-Line Results from Pivotal Trial of ARZERRA® (ofatumumab) Combined with Chlorambucil in Previously Untreated Chronic Lymphocytic Leukemia
GlaxoSmithKline (GSK) plc and Genmab A/S announced that their Phase III study of ARZERRA® (ofatumumab) in combination with chlorambucil versus chlorambucil alone in patients with previously untreated chronic lymphocytic leukemia met its primary endpoint of progression free survival as assessed by an independent review committee. [GlaxoSmithKline plc] Press Release

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NEW AABB Annual Meeting & CTTXPO 2013
October 12-15, 2013
Denver, United States

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