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Experimental Hematology

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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].

 

Effect of circadian variation on neutrophil mobilization to the peripheral blood in benign constitutional neutropeniaOpen in a New Window

Benign constitutional neutropenia (BCN), also known as benign ethnic neutropenia, is characterized by chronic neutropenia in non-Caucasian individuals who are apparently healthy and do not have a history of recurrent infections [1–3].

 

Characterization of inv(3) cell line OCI-AML-20 with stroma-dependent CD34 expressionOpen in a New Window

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by the abnormal proliferation and differentiation of hematopoietic stem cells. Patients diagnosed with AML often have a poor prognosis, with long-term survival being affected by subtype of disease, therapy given, and ability to tolerate treatment [1]. An important classifier of the disease that can predict response to therapy and outcome is the presence of recurrent cytogenetic abnormalities. Patients with recurrent 3q mutations such as inv(3)(q21q26.2) or t(3;3)(q21;q26.2) represent a subgroup of AML with a very poor prognosis due to the high rates of resistance to current chemotherapy regimens [2].

 

Establishment and characterization of immortalized erythroid progenitor cell lines derived from a common cell sourceOpen in a New Window

Recently, attempts have been made to produce large quantities of red blood cells (RBCs) in vitro using cell culture techniques [1–5]. Although hematopoietic stem/progenitor cells or pluripotent stem cells have been considered primary candidates for in vitro RBC production because they possess excellent characteristics for this technology [6–11], we have successfully established immortalized erythroid progenitor cell lines (imERYPCs) that can differentiate into enucleated RBCs [12]. The main advantage of these cell lines is that they can proliferate indefinitely, can produce enucleated RBCs rapidly, and can be handled with ease.

 

Loss of EfnB1 in the osteogenic lineage compromises their capacity to support hematopoietic stem/progenitor cell maintenanceOpen in a New Window

The bone marrow stromal microenvironment contributes to the maintenance and function of hematopoietic stem/progenitor cells (HSPCs). The Eph receptor tyrosine kinase family members have been implicated in bone homeostasis and stromal support of HSPCs. The present study examined the influence of EfnB1-expressing osteogenic lineage on HSPC function. Mice with conditional deletion of EfnB1 in the osteogenic lineage (EfnB1OB–/–), driven by the Osterix promoter, exhibited a reduced prevalence of osteogenic progenitors and osteoblasts, correlating to lower numbers of HSPCs compared with Osx:Cre mice.

 

Interleukin-18 plays a dispensable role in murine and likely also human bone marrow failureOpen in a New Window

Acquired aplastic anemia (AA) is a bone marrow (BM) failure syndrome characterized by peripheral blood (PB) pancytopenia and BM hypoplasia [1,2]. Success of immunosuppressive therapy (IST), among other clinical and laboratory clues, is compelling evidence of the immune pathophysiology of AA [3]. In most cases, AA is an immune-mediated disorder with active destruction of hematopoietic cells by effector T lymphocytes. Increased production of interferon gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) by patients’ T cells suggests important roles for a type 1 immune response in BM hematopoietic cell destruction [4–6].

 

TCF4 promotes erythroid developmentOpen in a New Window

Transcription factor 4 (TCF4, ITF2, E2-2) is a basic helix–loop–helix (bHLH) transcription factor that belongs to the family of E-box-binding proteins. These proteins recognize CANNTG (Ephrussi box) DNA sequences that are present in a variety of tissue-specific enhancers and promoters. E-proteins are widely expressed and can form both homodimers with other E-proteins or heterodimers with tissue-specific bHLH proteins. Dimerization of bHLH transcription factors results in the formation of a four-helix bundle, which allows the DNA-binding domains to associate with the E-box recognition site to regulate transcription [1].

 

Distinct pathways affected by menin versus MLL1/MLL2 in MLL-rearranged acute myeloid leukemiaOpen in a New Window

Patients with chromosomal translocations involving the Mixed Lineage Leukemia 1 gene (MLL, MLL1, KMT2A) represent an exception to overall favorable outcomes for children with acute leukemia [1]. Menin, which is encoded by the Men1 gene, is a tumor suppressor in neuroendocrine tissues but is essential for MLL1 fusion oncoprotein (MLL-FP)-mediated leukemogenesis. MLL-FP binding to menin bridges an interaction with Lens Epithelium-Derived Growth Factor (LEDGF), which in turn binds histone H3 dimethyl lysine 36 (H3K36me2)-modified chromatin [2,3].

 

A rare subgroup of leukemia stem cells harbors relapse-inducing potential in acute lymphoblastic leukemiaOpen in a New Window

After initially successful chemotherapy, relapse frequently jeopardizes the outcome of patients with acute leukemia. Because of their adverse characteristics of self-renewal and dormancy, leukemia stem cells have been hypothesized to play a critical role in resistance to antiproliferative chemotherapy and the development of relapse. The high abundance of stem-like cells in acute lymphoblastic leukemia (ALL), however, suggests that not all leukemia-initiating cells carry these adverse characteristics, complicating the biological characterization of relapse-inducing cells in this malignancy.

 

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 http://www.elsevier.com/locate/withdrawalpolicy.

 

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