Abstract:
OBJECTIVE:Polycythemia vera (PV) is characterized by erythrocytosis associated with the presence of the activating JAK2(V617F) mutation in a variable proportion of hematopoietic cells. JAK2(V617F) is detected in other myeloproliferative neoplasms, does not appear to be the PV-initiating event, and its specific role in deregulated erythropoiesis in PV is incompletely understood. We investigated the pathogenesis of PV to characterize abnormal proliferation and apoptosis responses and aberrant oncogenic pathway activation in primary PV erythroid precursors. MATERIALS AND METHODS:Peripheral blood CD34(+) cells isolated from PV patients and healthy controls were grown in liquid culture to expand a population of primary erythroblasts for experiments designed to analyze cellular proliferation, apoptosis, JAK2(V617F) mutation status, cytokine-dependent protein phosphorylation and gene expression profiling using Affymetrix microarrays. RESULTS:The survival and proliferation of PV erythroblasts were growth factor-dependent under strict serum-free conditions requiring both erythropoietin (EPO) and stem cell factor. PV erythroblasts exhibited EPO hypersensitivity and enhanced cellular proliferation associated with increased EPO-mediated extracellular signal-regulated kinases 1 and 2 phosphorylation. EPO-induced AKT phosphorylation was observed in PV but not normal erythroblasts, an effect associated with apoptosis resistance in PV erythroblasts. Analysis of gene expression and oncogenic pathway activation signatures revealed increased RAS (p<0.01) and phosphoinositide-3 kinase (p<0.05) pathway activation in PV erythroblasts. CONCLUSION:Deregulated erythropoiesis in PV involves EPO hypersensitivity and apoptosis resistance of erythroid precursor cells associated with abnormally increased activation of RAS-ERK and phosphoinositide-3 kinase-AKT pathways. These data suggest that investigation of the mechanisms of abnormal RAS and phosphoinositide-3 kinase pathway activation in erythroblasts may contribute to our understanding of the molecular pathogenesis of PV.
journal_name
Exp Hematoljournal_title
Experimental hematologyauthors
Laubach JP,Fu P,Jiang X,Salter KH,Potti A,Arcasoy MOdoi
10.1016/j.exphem.2009.09.009subject
Has Abstractpub_date
2009-12-01 00:00:00pages
1411-22issue
12eissn
0301-472Xissn
1873-2399pii
S0301-472X(09)00389-0journal_volume
37pub_type
杂志文章abstract:OBJECTIVE:Hematopoietic progenitor cells are a promising source for generation of genetically modified dendritic cells. A prerequisite for using these cells in therapeutic approaches is stable vector-mediated transgene expression during and after cell maturation. We investigated the expression of enhanced green fluores...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(01)00778-0
更新日期:2002-02-01 00:00:00
abstract::Hepcidin is the key regulator of iron absorption and recycling, and its expression is suppressed by red blood cell production. When erythropoiesis is expanded, hepcidin expression decreases. To gain insight into the stage of erythroid differentiation at which the regulation might originate, we measured serum hepcidin ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2015.03.001
更新日期:2015-06-01 00:00:00
abstract::Erythropoiesis requires large amounts of iron for hemoglobin synthesis. There are two sources of iron for erythropoiesis, dietary and stored iron; however, their relative contributions to erythropoiesis remain unknown. In this study, we used the stable iron isotope (57)Fe to quantify synthesis of hemoglobin derived fr...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2016.02.005
更新日期:2016-06-01 00:00:00
abstract::When cultured mast cells of (WB X C57BL/6)F1-+/+(WBB6F1-+/+) and WB-+/+(WB) mice were directly injected into the skin of genetically mast cell-deficient WBB6F1-W/Wv mice, mast cell clusters appeared at the injection sites. Although in vitro colony-forming ability is comparable between cultured mast cells of WB mice an...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1988-12-01 00:00:00
abstract:OBJECTIVE:We studied two adult brothers with severe congenital thrombocytopenia in order to determine the genetic etiology of their inherited disorder. Despite the absence of eczema or immunodeficiency, a mutation of the Wiskott-Aldrich syndrome (WAS) gene was suspected because of the presence of microthrombocytes. MA...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(02)01023-8
更新日期:2003-02-01 00:00:00
abstract::It is becoming increasingly clear that the adeno-associated virus 2 (AAV)-based vector system may prove to be useful for high-efficiency gene transfer in human cells as well as for potential gene therapy in humans. A recombinant AAV vector containing the gene for a human hematopoietic growth factor, granulocyte-macrop...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1995-11-01 00:00:00
abstract::The fate of hematopoietic progenitor cells (HPCs) in the bone marrow (BM) microenvironment is determined by two different interactions: 1) they adhere (via integrins) to both extracellular matrix molecules and BM stromal cells; and 2) stromal cells produce cytokines that influence their survival, proliferation, differ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1998-08-01 00:00:00
abstract:OBJECTIVE:Recent clinical trials of adoptive immunotherapy showed diminished reactivity of human T cells upon ex vivo manipulation. For a safe and effective clinical application of human T cells, it is necessary to improve ex vivo manipulation procedures and evaluate their impact on in vivo functionality. However, ther...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2006.09.018
更新日期:2007-01-01 00:00:00
abstract::Marked loss of colony stimulating activity was noted when the highly purified human urinary colony stimulating factor (CSFHU-5) dissolved in 0.1 M Tris-HCl buffer (pH 7) was passed through ethylene oxide sterilized Millipore filters. The addition of 0.5 mg/ml polyethylene glycol (PEG) or 10 mg/ml bovine serum albumin ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1983-05-01 00:00:00
abstract:OBJECTIVE:TGF-beta1 is a powerful inhibitor of erythropoiesis. However, its mechanisms of action are not fully elucidated yet at the cellular level. In this work we have studied the effects of TGF-beta on UT-7 cell survival, proliferation and differentiation. MATERIALS AND METHODS:UT-7 cell line is strictly dependent ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(99)00155-1
更新日期:2000-03-01 00:00:00
abstract::The effects of the inhibition of the cyclooxygenase and lipoxygenase metabolic pathways of arachidonic acid on the postirradiation recovery of hematopoietic functions in mice were investigated. Nordihydroguaiaretic acid (NDGA), an inhibitor of prostaglandin (PG) and leukotriene (LT) production, was given to animals in...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1993-01-01 00:00:00
abstract::The renal tumor RCC-3-JCK, when transplanted into immunodeficient mice, caused an erythrocytic polycythemia. When grown in culture, the tumor cells secreted a substance into the culture medium that chromatographed by size-exclusion high-performance liquid chromatography similarly to purified human erythropoietin (Ep) ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1985-01-01 00:00:00
abstract::Bone marrow hematopoietic progenitors (CFU-GM, CFU-E, and BFU-E) were found to be markedly decreased in 21 bone marrow transplant recipients studied from one to 51 months after transplantation. In these patients, bone marrow colony formation could be significantly enhanced by in vitro incubation of the bone marrow tar...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1986-08-01 00:00:00
abstract::The cycle specific drug, hydroxyurea (HU), has previously been used to study the proliferative kinetics of various hemopoietic precursor cells such as granulocyte-macrophage precursors (CFUc) and multipotential stem cells (CFUs). We have investigated the kinetics of another hemopoietic precursor, a T-cell colony (CFUT...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1980-05-01 00:00:00
abstract::Type IV nuclear bodies are classified as true intranuclear inclusions that ultrastructurally contain numerous densely packed 20- to 30-nm osmiophilic granules surrounded by a microfibrillar cortex. In the present study, we have found statistically significant ultrastructural differences in the frequency and size of ty...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1987-02-01 00:00:00
abstract:OBJECTIVE:Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia caused by mutations in ribosomal protein (RP) genes. Our aim is to develop gene therapy for DBA patients with mutations in RPS19. We previously demonstrated that RPS19 gene transfer partially corrects erythroid development in vitro. In this...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2008.06.012
更新日期:2008-11-01 00:00:00
abstract::The statistical distribution of colony counts in the spleen colony assay was determined in C57BL/6 and C3H mice under varying conditions of the assay procedure. Assay mice were given syngeneic bone marrow cells from normal or irradiated donors. The mice were injected intravenously with marrow cells either immediately ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1977-11-01 00:00:00
abstract::Lentinan, an antitumor polysaccharide, has been assessed for its potential in vivo to augment erythroid progenitor cells and protect them from the cytotoxic effects of antitumor chemotherapeutics. Lentinan augmented the level of burst-forming units-erythroid (BFU-E) and accelerated the recovery of the reduced number o...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1996-02-01 00:00:00
abstract::The aberrant overexpression of Wilms tumor-1 (WT1) in acute myeloid leukemia (AML) plays an important role in blast cell survival by enhancing proliferation and inhibiting apoptosis. However, the mechanism underlying the overexpression of WT1 remains unclear. Here, we identified miR-193a (miR-193a-5p) and miR-600 targ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2018.02.001
更新日期:2018-05-01 00:00:00
abstract::A thymic stromal cell line with a medullary phenotype (Z210R.1) supported the differentiation of surface IgM+ B cells when cocultured with fetal liver cells in vitro. Conditioned medium (CM) from this cell line supported the long-term growth of a B cell line (NAG8/7) isolated from cocultures and enhanced the prolifera...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::Mds1-Evi1 (also known as Prdm3) and Prdm16 are two highly related zinc finger transcription factors that, within the hematopoietic system, are both expressed primarily in hematopoietic stem cells (HSCs). Our laboratory previously found that constitutive Mds1-Evi1 knockout mice are viable, but their HSCs are unable to ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2020.04.010
更新日期:2020-05-01 00:00:00
abstract::A cell line (LAMA-84) has been established from the blood of a patient with chronic myeloid leukemia in acute phase. LAMA-84 cells retained the patient's chromosome abnormalities, i.e., triplication of all chromosomes except chromosome 18, the presence of Philadelphia (Ph) chromosome in 4-5 copies, and the presence of...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1987-09-01 00:00:00
abstract:OBJECTIVE:Limitin is a new member of type I interferon (IFN) identified with an expression cloning based on the growth suppression of a myelomonocytic leukemia cell line WEHI3. Although limitin uses the IFN-alpha/beta receptor, its signal transduction pathways to express the antiviral effects are different from those o...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2004.06.008
更新日期:2004-09-01 00:00:00
abstract::[3H]thymidine uptake by NFS-60 cells in microcultures was found to increase in a linear fashion with the increasing doses of purified recombinant human granulocyte colony-stimulating factor (rhG-CSF). Such increases were found neither with rhG-CSF samples pretreated with rabbit anti-rhG-CSF serum nor with other human ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1989-02-01 00:00:00
abstract::A simple two-step procedure has been developed for the production of human urinary erythropoietin suitable for tissue culture use. Lyophilized human urinary protein was fractionated by phenyl-Sepharose chromatography, the erythropoietin binding in 2 M lithium chloride and being eluted by an ascending linear gradient t...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1985-09-01 00:00:00
abstract:OBJECTIVE:We have previously shown that Flt3 ligand (FL)/Flt3 signaling regulates hematopoietic cell migration by modulating the SDF1alpha/CXCR4 signaling pathway. Herein, we evaluated whether a functional interaction between SDF1alpha/CXCR4 signaling and internal tandem duplication (ITD) of Flt3 regulates aberrant hem...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2006.04.001
更新日期:2006-08-01 00:00:00
abstract:OBJECTIVE:Several transcription factors determine the cell fate decision between granulocytes and monocytes, but the upstream signal transduction pathways that govern myelopoiesis are largely unknown. Based on our observation of aberrant myeloid cell representation in hematopoietic tissues of 12/15-lipoxygenase (12/15-...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2010.07.004
更新日期:2010-11-01 00:00:00
abstract:OBJECTIVE:To design a culture method allowing the quantitative and qualitative analysis of terminal erythroid differentiation. METHODS:Primary erythroid progenitors derived either from mouse tissues or from human umbilical cord blood were differentiated using hanging drop cultures and compared to methylcellulose cultu...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2005.06.014
更新日期:2005-10-01 00:00:00
abstract::We previously demonstrated that lysis of tumor cells that express Hsp70, the highly stress-inducible member of the HSP70 family, on their plasma membrane is mediated by natural killer (NK) cells. Here, we studied the effects of different proteins of the HSP70 family in combination with interleukin 2 (IL-2) on the prol...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(99)00104-6
更新日期:1999-11-01 00:00:00
abstract:OBJECTIVE:To investigate the mechanisms of antiproliferative effect induced by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus in mantle cell lymphoma (MCL). MATERIALS AND METHODS:The antiproliferative effect of temsirolimus on three well-defined MCL cell lines was examined by the MTS assay. Induction ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2007.12.008
更新日期:2008-04-01 00:00:00