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The seminal discovery of cell reprogramming in 2006 by Shinya Yamanaka opened up novel and unprecedented perspectives not only in the field of biology in general, but also in all fields of medicine, with almost endless possibilities in terms of therapeutic applications [1]. Although the use induced pluripotent stem cells (iPSC) appeared initially as a technique that would be widely applicable alternatives to embryonic stem cells (ESC), several hurdles remain to be solved for the use of iPSC and their derivatives in regenerative medicine.


Induced pluripotent stem cell modeling of malignant hematopoiesisOpen in a New Window

In 2012 the Nobel Prize in Physiology or Medicine was awarded to Sir John Gurdon and Shinya Yamanaka for the discovery that mature differentiated cells could be reprogrammed to a pluripotent state. By introducing four transcription factors (Sox2, Klf4, Oct3/4, and c-Myc), terminally differentiated cells can be epigenetically reprogrammed to an undifferentiated state [1]. Importantly, this epigenetic process does not alter the underlying genetic code of the parent cell. As such, these induced pluripotent stem cells (iPSCs) have significant applications in disease biology, including the ability to create novel disease models of human genetic disease for biologic discovery.


Sphingosine-1-phosphate Signaling Modulates Terminal Erythroid Differentiation through the Regulation of MitophagyOpen in a New Window

Erythropoiesis, the process of differentiation from hematopoietic/stem progenitor cells (HSPCs) to mature red blood cells (RBCs), is responsible for the daily production of ∼2 × 1011 RBCs to maintain homeostatic oxygen supply to various tissues [1, 2]. Adult erythropoiesis occurs in the bone marrow via three stages: early erythropoiesis, terminal erythroid differentiation and reticulocyte maturation [1, 3]. Early erythropoiesis involves the differentiation of HSPCs into megakaryocyte-erythroid progenitors (MEP), followed by burst-forming unit-erythroid (BFU-E), colony-forming unit-erythroid (CFU-E), and finally proerythroblasts [4].


USP44 is dispensable for normal hematopoietic stem cell function, lymphocyte development, and B cell mediated immune response in a mouse modelOpen in a New Window

Most cells of our blood and immune system are produced from hematopoietic stem cells (HSCs) in the bone marrow through the process of cell proliferation and differentiation, known as hematopoiesis. Immune response against infection or immunization involves multiple further cell proliferation, differentiation, and activation checkpoints. Dysregulation in the molecular mechanisms controlling cell cycle progression, gene expression, and genomic stability in hematopoietic and immune cells is commonly linked to bone marrow failure, immunodeficiency, and cancer.


Human iPSC-based model of severe congenital neutropenia reveals elevated UPR and DNA damage in CD34+ cells preceding leukemic transformationOpen in a New Window

Severe congenital neutropenia (CN) is a monolineage preleukemia bone marrow failure syndrome characterized by early onset of neutropenia and severe infections due to promyelocytic maturational arrest in the bone marrow [1,2]. CN is a heterogeneous disease caused by mutations in a number of genes, including ELANE [3] (the most common [1]), HAX1 [4], CSF3R [5,6], JAGN1 [7], G6PC3 [8], TCIRG1 [9], and others. In most cases, ELANE mutations are missense mutations that are distributed throughout all five exons of the ELANE gene, although a majority of mutations are found in exons 4 and 5 [10].


Compounds targeting class II histone deacetylases do not cause panHDACI-associated impairment of megakaryocyte differentiationOpen in a New Window

The first generation of histone deacetylase inhibitors (HDACIs) has shown significant efficacy in the inhibition of cancer cell proliferation both in in vitro and in xenograft in vivo models. These inhibitors are generally broad acting (pan), inhibiting a number of histone deacetylases (HDACs) with increasing class preference depending on the concentration. Currently, four panHDACIs—suberoyl anilide hydroxamic acid (SAHA), panobinostat, romidepsin, and belinostat—have been approved by the Food and Drug Administration as epigenetic therapies, mainly for the treatment of T-cell lymphomas and multiple myelomas.


Development of innate immune cells from human pluripotent stem cellsOpen in a New Window

Mouse and human pluripotent stem cells have been widely used to study the development of the hematopoietic and immune systems. Although not all cells can be derived with the same efficiency, immune cells such as natural killer (NK) cells and macrophages can be easily produced from PSCs to enable development of new cell-based therapies. NK cells and macrophages are part of the innate immune system, the first line of defense against malignancies and infectious disease. Human embryonic stem cell (hESC)- and induced pluripotent stem cell (iPSC)-derived NK cells can be produced at a clinical scale suitable for translation into clinical trials.


Functional interdependence of hematopoietic stem cells and their niche in oncogene promotion of myeloproliferative neoplasms: The 159th biomedical version of “it takes two to tango”Open in a New Window

The role of stem cells in normal and neoplastic hematopoiesis is well established. However, neither normal nor neoplastic hematopoietic stem cells (HSCs) develop in isolation and accumulating evidence indicates that a critical developmental role is played by the perivascular “niche.” The cellular, humoral, and cell surface contacts that provide the proper environment for HSC survival, proliferation, and differentiation are becoming increasingly better understood. A number of studies have established that endothelial cells (ECs), several types of perivascular stromal cells, and megakaryocytes (MKs) provide several cell surface and secreted molecules required for HSC development.


Targeting Cell-bound MUC1 on Myelomonocytic, Monocytic Leukemias and Phenotypically Defined Leukemic Stem Cells with Anti-SEA Module AntibodiesOpen in a New Window

Cell surface molecules aberrantly expressed or overexpressed by myeloid leukemic cells represent potential disease-specific therapeutic targets for antibodies. MUC1 is a polymorphic glycoprotein, the cleavage of which yields two unequal chains: a large extracellular α subunit containing a tandem repeat array bound in a strong noncovalent interaction to a smaller β subunit containing the transmembrane and cytoplasmic domains. Because the α-chain can be released from the cell-bound domains of MUC1, agents directed against the α-chain will not effectively target MUC1+ cells.


MISTRG Mice Support Engraftment and Assessment of Nonhuman Primate Hematopoietic Stem and Progenitor CellsOpen in a New Window

Preclinical feasibility, safety, and efficacy testing of hematopoietic stem cell (HSC)-mediated gene therapy approaches is commonly performed in large-animal models such as nonhuman primates (NHPs). Here, we wished to determine whether mouse models would allow engraftment of NHP HSPCs, which would enable more facile and less costly evaluation of promising strategies. In this study, we comprehensively tested two mouse strains for the engraftment of NHP CD34+ hematopoietic stem and progenitor cells (HSPCs).


From Pluripotent Stem Cells to T cellsOpen in a New Window

The generation of T cells from human pluripotent stem cells (PSCs) opens a valuable experimental window into developmental hematopoiesis and raises the possibility of a new therapeutic approach for T-cell immunotherapy. After directing PSCs through mesoderm and early hematopoietic developmental stages, commitment to the T-cell lineage has been achieved by several groups using coculture with stromal cells that express a notch ligand, recapitulating the critical signals that initiate the first stages of normal T-cell differentiation in the thymus.


Smc3 is required for mouse embryonic and adult hematopoiesisOpen in a New Window

SMC3 encodes a subunit of the cohesin complex that has canonical roles in regulating sister chromatids segregation during mitosis and meiosis. Recurrent heterozygous mutations in SMC3 have been reported in acute myeloid leukemia (AML) and other myeloid malignancies. In this study, we investigated whether the missense mutations in SMC3 might have dominant-negative effects or phenocopy loss-of-function effects by comparing the consequences of Smc3-deficient and -haploinsufficient mouse models. We found that homozygous deletion of Smc3 during embryogenesis or in adult mice led to hematopoietic failure, suggesting that SMC3 missense mutations are unlikely to be associated with simple dominant-negative phenotypes.


Arterial identity of hemogenic endothelium: a key to unlock definitive hematopoietic commitment in hPSC culturesOpen in a New Window

Human pluripotent stem cells (hPSCs) have been suggested as a potential source for the de novo production of blood cells for transfusion, immunotherapies, and transplantation. However, even with advanced hematopoietic differentiation methods, the primitive and myeloid-restricted waves of hematopoiesis dominate in hPSC differentiation cultures, whereas cell surface markers to distinguish these waves of hematopoiesis from lympho-myeloid hematopoiesis remain unknown. In the embryo, hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries, but not veins.


Modeling myeloid malignancies with patient-derived iPSCsOpen in a New Window

The derivation of human induced pluripotent stem cells (iPSCs) in 2007 ushered in a new era in the modeling of human diseases, including those affecting the hematopoietic system [1–3]. Significant advances over the past decade have enabled investigators to increasingly incorporate iPSC models in their research. iPSCs can empower diverse research studies, ranging from investigations into basic disease mechanisms to more translational applications such as therapeutic target discovery, drug testing, compound screening, toxicity testing, and generation of cells for transplantation [2,4].


The case for plerixafor to replace filgrastim as the optimal agent to mobilize peripheral blood donors for allogeneic hematopoietic cell transplantationOpen in a New Window

Currently, the predominant approach to accessioning donor cells for hematopoietic cell transplantation (HCT) is the use of granulocyte colony-stimulating factor (G-CSF) treatment of the donor for a number of days, followed by leukapheresis of peripheral blood progenitor cells (G-PBs) [1]. Over 70% of adult allogeneic HCT procedures utilize G-PBs in the United States and Canada [2]. Studies have shown that allogeneic transplantation with unstimulated bone marrow (BM) allograft results in lower rates of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and improved quality of life compared with G-PB grafts [1–3].


Deferasirox selectively induces cell death in the clinically relevant population of leukemic CD34+CD38– cells through iron chelation, induction of ROS, and inhibition of HIF1α expressionOpen in a New Window

Acute myelogenous leukemia (AML) is a clonal malignancy that is thought to be initiated at a stage as early as hematopoietic stem/progenitor cells [1]. The cure rates are less than 10% for older AML patients and the median survival is less than 1 year for these patients [2]. Although 70–80% of younger patients achieve complete remission, most will eventually relapse and overall survival is only 40–50% at 5 years [3,4]. Drug resistance and relapse are major causes for treatment failure. Current treatments for AML such as nucleoside analogs (e.g., cytosine arabinoside [ARA-C]) and anthracyclines [e.g., idarubicin, daunorubicin]) interfere with DNA replication and induce apoptosis primarily in replicating cells [4,5].


MIR-144-mediated NRF2 gene silencing inhibits fetal hemoglobin expression in sickle cell diseaseOpen in a New Window

Sickle cell disease (SCD) is a genetic disorder caused by the βS-globin mutation leading to production of hemoglobin S, polymer formation under low oxygen conditions, and red blood cell sickling. The net outcome of this process is chronic hemolysis, oxidative stress, anemia, and vaso-occlusive episodes of pain and organ damage. The most effective treatment for SCD is fetal hemoglobin (HbF; α2γ2) induction, which inhibits sickle hemoglobin polymerization through the formation of hybrid molecules [1].


Modeling human RNA spliceosome mutations in the mouse: not all mice were created equalOpen in a New Window

Myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and related disorders are a heterogeneous class of blood cancers leading to ineffective hematopoiesis in the bone marrow (BM) [1,2]. Approximately 30% of MDS patients progress to acute leukemia. Median survival ranges from 97 months for low-risk categories down to 11 months for high-risk MDS [2]. The incidence of MDS in the general population is approximately four to five per 100,000 people, but this increases with age [1].


CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p–XIAP axisOpen in a New Window

Acute myeloid leukemia (AML) is one of the most common hematological malignancies [1,2]. Despite the application of new molecular targeted drugs and progress of allogeneic hematopoietic stem cell transplantation, chemoradiotherapy is still the mainstay for the treatment of AML. However, AML cells are demonstrated to unavoidably develop primary or secondary chemoresistance, thereby resulting in refractory and recurrent disease in patients. So far, most clinical trials of chemotherapy have shown very limited benefits for refractory and recurrent AML [3].


WITHDRAWN: Assessment of hematopoietic and neurologic pathophysiology of HCLS1-associated protein X-1 deficiency in a Hax1-knockout mouse modelOpen in a New Window

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause.The full Elsevier Policy on Article Withdrawal can be found at


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