Hematopoiesis News Volume 4.15 | Apr 23 2013

LABORATORY RESEARCH

Pluripotent Stem Cell Models of Shwachman-Diamond Syndrome Reveal a Common Mechanism for Pancreatic and Hematopoietic Dysfunction
Investigators created human pluripotent stem cell models of Shwachman-Diamond syndrome (SDS) through knockdown of the Shwachman-Bodian-Diamond syndrome (SBDS) gene in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two patients with SDS. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis, and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors. [Cell Stem Cell] Abstract

The Expression of Sox17 Identifies and Regulates Hemogenic Endothelium
Researchers identified Sox17 as a key regulator of hemogenic endothelial development. Analysis of Sox17-GFP reporter mice revealed that Sox17 is expressed in hemogenic endothelium and emerging hematopoietic stem cells (HSCs) and that it is required for HSC development. [Nat Cell Biol] Abstract

Ldb1-Nucleated Transcription Complexes Function as Primary Mediators of Global Erythroid Gene Activation
Scientists generated a genome-wide map of Ldb1-complex binding sites that revealed widespread binding at erythroid genes and at known erythroid enhancer elements. The results provide a foundation for defining the mechanism and scope of Ldb1-complex activity during erythropoiesis. [Blood] Abstract

Autocrine Signaling Based Selection of Combinatorial Antibodies that Transdifferentiate Human Stem Cells
Researchers reported the generation of antibody agonists from intracellular combinatorial libraries that transdifferentiate human stem cells. Unlike the natural granulocyte-colony stimulating factor that activates cells to differentiate along a predetermined pathway, the isolated agonist antibodies transdifferentiated human myeloid lineage CD34+ bone marrow cells into neural progenitors. [Proc Natl Acad Sci USA]
Abstract | Press Release

A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells In Vivo
The authors performed a large-scale chemical library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate hematopoietic cell kinase inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC₅₀ in the subnanomolar range. In vivo administration of RK-20449 to nonobese diabetic/severe combined immunodeficient/IL2rg^null mice engrafted with highly aggressive therapy-resistant acute myeloid leukemia (AML) significantly reduced human leukemia stem cell and non-stem AML burden. [Sci Transl Med]
Abstract | Press Release

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of CN-AML
Investigators demonstrated that the HDAC inhibitor Entinostat inhibits disease maintenance and prolongs survival in a clinically relevant murine model of cytogenetically normal acute myeloid leukemia (CN-AML). [Stem Cells] Abstract

Calcium-Dependent Permeabilization of Erythrocytes by a Perforin-Like Protein during Egress of Malaria Parasites
Clinical malaria is associated with proliferation of blood-stage parasites. During the blood stage, Plasmodium parasites invade host red blood cells, multiply, egress and reinvade uninfected red blood cells to continue the life cycle. Researchers demonstrated that calcium-dependent permeabilization of host red blood cells is critical for egress of Plasmodium falciparum merozoites. [Nat Commun] Abstract

Extracellular Matrix-Modulated Heartless Signaling in Drosophila Blood Progenitors Regulates their Differentiation via a Ras/ETS/FOG Pathway and Target of Rapamycin Function
Investigators examined the function of the Drosophila Fibroblast Growth Factor Receptor, Heartless, a critical regulator of early lymph gland progenitor specification in the late embryo, during larval lymph gland hematopoiesis. [Dev Biol] Abstract

CLINICAL RESEARCH

A Phase III Study of Gemtuzumab Ozogamicin during Induction and Post-Consolidation Therapy in Younger Patients with Acute Myeloid Leukemia
This randomized phase III clinical trial evaluated the potential benefit of the addition of gemtuzumab ozogamicin to standard induction and post-consolidation therapy in patients with acute myeloid leukemia. [Blood] Abstract

CSF3R T618I Is a Highly Prevalent and Specific Mutation in Chronic Neutrophilic Leukemia
In order to clarify mutational frequency, specificity and phenotypic associations, researchers sequenced the receptor cytoplasmic domain for colony stimulating factor 3 (CSF3R) exons 14-17 in 54 clinically suspected cases of chronic neutrophilic leukemia or atypical chronic myeloid leukemia. [Leukemia] Abstract

The Biological Rationale and Clinical Efficacy of Inhibition of Signaling Kinases in Chronic Lymphocytic Leukemia
Researchers focus on the microenvironmental interactions of chronic lymphocytic leukemia and the role of tyrosine kinases. [Leuk Res] Abstract

MicroRNAs and B Cell Receptor Signaling in Chronic Lymphocytic Leukemia
The authors review studies that provide evidence suggesting that certain microRNAs (miRNAs) can regulate the activated phenotype of chronic lymphocytic leukemia (CLL) cells and/or the fitness of surface-immunoglobulin B cell receptor complex expressed by CLL cells, thereby accounting for the differential leukemia-cell-expression of these miRNAs in different CLL prognostic-subgroups. [Leuk Lymphoma] Abstract

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

Pharmacyclics Completes Enrollment of First Phase III Ibrutinib CLL Study – RESONATE™ and Announces Completion of Enrollment of Phase II Ibrutinib MCL Study – SPARK
Pharmacyclics, Inc. announced that the enrollment target of 350 patients for its Phase III study using ibrutinib monotherapy versus ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), (RESONATE™) was achieved. An additional 41 patients were screened and are allowed to participate in this study which has now been officially closed to enrollment. [Pharmacyclics, Inc.] Press Release

Stem Cell Therapeutics Licenses Exclusive Rights to Clinical Cancer Stem Cell Program
Stem Cell Therapeutics Corp. (SCT) announced the execution of a definitive license agreement with University Health Network, Toronto, Canada. The agreement, developed in collaboration with MaRS Innovation, provides Stem Cell Therapeutics with exclusive worldwide rights to an innovative clinical cancer stem cell program. The technology licensed by SCT is based on Dr. Aaron Schimmer’s discovery that an FDA-approved antibiotic, tigecycline, selectively targets leukemia cells and leukemic stem cells by inhibiting mitochondrial protein synthesis and thus shutting down the cells energy supply. [Stem Cell Therapeutics Corp.] Press Release

Cancer Treatment Pioneers to Share America’s Most Distinguished Prize
Three physician scientists whose landmark research helped transform the treatment of cancer are the recipients of the prestigious Albany Medical Center Prize in Medicine and Biomedical Research. This year, the prize will recognize groundbreaking research into the nature of cancer, which has led to the development of a new generation of cancer drugs, most notably Gleevec for chronic myeloid leukemia that, unlike chemotherapy, target specific genetic defects causing cancer. [Albany Medical Center] Press Release

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