Abstract：
:The tumor suppressor p53 is thought to play a role in megakaryocyte (MK) development. To assess the influence of the p53 regulatory pathway further, we studied the effect of RG7112, a small molecule MDM2 antagonist that activates p53 by preventing its interaction with MDM2, on normal megakaryocytopoiesis and platelet production. This drug has been previously been evaluated in clinical trials of cancer patients where thrombocytopenia was one of the major dose-limiting toxicities. In this study, we demonstrated that administration of RG7112 in vivo in rats and monkeys results in thrombocytopenia. In addition, we identified two distinct mechanisms by which RG7112-mediated activation of p53 affected human megakaryocytopoiesis and platelet production in vitro. RG7112 promoted apoptosis of MK progenitor cells, resulting in a reduction of their numbers and RG7112 affected mature MK by blocking DNA synthesis during endomitosis and impairing platelet production. Together, the disruption of these events provides an explanation for RG7112-induced thrombocytopenia and insight into the role of the p53-MDM2 auto-regulatory loop in normal megakaryocytopoiesis.
journal_name
Exp Hematoljournal_title
Experimental hematologyauthors
Iancu-Rubin C,Mosoyan G,Glenn K,Gordon RE,Nichols GL,Hoffman Rdoi
10.1016/j.exphem.2013.11.012subject
Has Abstractpub_date
2014-02-01 00:00:00pages
137-45.e5issue
2eissn
0301-472Xissn
1873-2399pii
S0301-472X(13)00921-1journal_volume
42pub_type
杂志文章abstract：:The etiology of thrombocytopenia is important in treatment and management of the condition. Most platelet parameters that are routinely analyzed in the diagnostic laboratory have not proven useful in identifying the etiology, while specialized assays suffer from poor standardization and lack of agreement between labor...
journal_title：Experimental hematology
pub_type： 临床试验,杂志文章,多中心研究
doi：10.1016/j.exphem.2019.09.001
更新日期：2019-10-01 00:00:00
abstract：:Acute disseminated intravascular coagulation (DIC) is a life-threatening condition that may be encountered in many situations, especially in cases of shock with uncontrollable hemorrhage. Anisodamine, an alkaloid extracted from a Chinese herb, is well known for its dramatic therapeutic effect on DIC. Sixty male rabbit...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1987-01-01 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
abstract：:Differentiation- and lineage-related differences in the expression of two anti-apoptotic molecules, bcl-x and bcl-2, were examined using various human hematopoietic cell lines. Bcl-x was strongly expressed in cell lines with erythroid and megakaryocytic properties (K562, HEL, CMK, and Mo7E), and was moderately express...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1998-03-01 00:00:00
abstract：:G-banded metaphase chromosomes prepared from 14 male CBA/Ca mice with histologically confirmed myeloid leukemia (ML) were studied in an effort to identify specific chromosomal changes associated with radiation leukemogenesis. The chromosome studies were undertaken as part of a larger investigation of radiation carcino...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1993-03-01 00:00:00
abstract：:Addition of serum or plasma from many species increased the number and size of neutrophilic granulocyte and macrophage colonies formed in vitro by mouse bone marrow cells after stimulation by a variety of preparations containing colony stimulating factor (CSF). The active factor in serum was heat-labile, non-dialyzabl...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1975-08-01 00:00:00
abstract：OBJECTIVE:To test gibbon ape leukemia virus (GALV) pseudotype vector transduction of marrow subpopulations that contribute to hematopoietic reconstitution in vivo. MATERIALS AND METHODS:Autologous CD34(+) Lin(-), CD34(+) Lin(+), and CD34(-) Lin(-) marrow cells, transduced by coculture with PG13/LN, PG13/LNX, and PG13/...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/s0301-472x(00)00137-5
更新日期：2000-05-01 00:00:00
abstract：OBJECTIVE:Haplotype-mismatched CD34(+) selected allogeneic stem cell transplantation (HASCT) has been described as a therapeutic option for patients with acute myeloid leukemia. The success of this regimen is based mainly on natural killer (NK) cell-mediated antileukemia effects. MATERIALS AND METHODS:We prospectively...
journal_title：Experimental hematology
pub_type： 临床试验,杂志文章
doi：10.1016/j.exphem.2007.12.006
更新日期：2008-04-01 00:00:00
abstract：:The pool size of erythroid burst-(BFUe) and colony-forming units (CFUe) has been evaluated in normal or hypoxia-induced polycythemic mice at sequential times after either transfusion or administration of purified erythropoietin (Ep). The present investigations were focused on the in vitro tritiated thymidine (3H-TdR) ...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1980-01-01 00:00:00
abstract：:Stem cell maintenance in continuous bone marrow culture has been shown to be associated with close range interaction between hematopoietic cells and marrow derived adherent cells (MDAC). The extent to which the culture system is dependent upon this type of interaction has not been ascertained. Explants of non-adherent...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1981-03-01 00:00:00
abstract：:Heterozygous alpha-thalassemic (Hbath/+) female mice were investigated for the effect of persistent erythropoietic stress on the number of stem cells and progenitor cells along the the erythroid (E), granulocyte-macrophage (GM), and megakaryocyte (Meg) pathways. At the progenitor cell level, compensatory erythropoiesi...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1986-05-01 00:00:00
abstract：OBJECTIVE:Differentiation-inducing therapy by agents such as 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) represents a useful approach for the treatment of acute myelogenous leukemia (AML). We previously showed that Gemini-23-yne-26,27-hexafluoro-D(3) inhibited the proliferation of MCF-7 breast cancer cells in associat...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/j.exphem.2010.03.020
更新日期：2010-08-01 00:00:00
abstract：:As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML g...
journal_title：Experimental hematology
pub_type： 杂志文章,评审
doi：10.1016/j.exphem.2015.05.009
更新日期：2015-08-01 00:00:00
abstract：:Seven patients received cancer chemotherapy with high-dose cyclophosphamide (HD-CTX) associated with either recombinant human granulocyte colony-stimulating factor (rhG-CSF), rh interleukin-3 (rhIL-3), rh granulocyte-macrophage CSF (rhGM-CSF) plus rh erythropoietin (rhEpo), rhIL-3 plus rhGM-CSF, or rhIL-3 plus rhG-CSF...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1993-11-01 00:00:00
abstract：:The production of interferon-alpha (IFN-alpha) by normal human peripheral blood mononuclear cells (PBMNC) was studied using polyclonal antipeptide antibodies designed to react either with all IFN-alpha subtypes or with individual subtypes IFN-alpha 2 or IFN-alpha 4. In this study, we demonstrate the detection of intra...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1995-03-01 00:00:00
abstract：:Persistent reductions in the femoral content of hemopoietic colony-forming cells (CFU-S and GM-CFC) were observed after four doses of irradiation, delivered with three weeks between doses. In general, the reductions were dose dependent, and similar reductions were produced by single doses and repeated doses using the ...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1986-03-01 00:00:00
abstract：OBJECTIVE:Based on previous animal experiments that suggest the plasticity of peripheral blood-derived, CD34(-) stem cell lines, the aim of this study was to isolate CD34(-) stem cell lines from human peripheral blood cells and obtain evidence of their multipotency and plasticity. MATERIALS AND METHODS:Adherent growin...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/s0301-472x(02)00865-2
更新日期：2002-08-01 00:00:00
abstract：OBJECTIVE:The ABCG2 transporter has been identified as a determinant of the side population (SP) in murine bone marrow and a potential marker for primitive stem cells. To assess the potential of the SP phenotype and ABCG2 expression to identify stem cells in human umbilical cord blood (hUCB), we have examined directly ...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/j.exphem.2008.09.015
更新日期：2009-02-01 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：OBJECTIVE:MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs that regulate diverse cellular functions by sequence-specific inhibition of gene expression. We determined miRNA expression profile during erythroid differentiation and putative roles in erythroid differentiation. METHODS:The expression profile...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/j.exphem.2007.03.014
更新日期：2007-07-01 00:00:00
abstract：:Although macrophages account for 70-90% of the adherent cells in mouse long-term bone marrow cultures (LTBMC) and CFU-F colonies, the predominant nonhematopoietic stromal cell is endothelial-like (EL), expressing cytoplasmic collagen IV, laminin, and an antigen recognized by the monoclonal antibody MECA-10. We report ...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1995-12-01 00:00:00
abstract：:We investigated whether gene transfer into hematopoietic cells could be achieved by direct injection of retroviral vector supernatant into the bone marrow space of newborn sheep. Six sheep (5 weeks old) were injected bilaterally with either 1 mL of G1nBgSvNa8.1 vector supernatant (titer: 1 x 10(7)) in each hip (n = 5)...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/s0301-472x(00)00158-2
更新日期：2000-06-01 00:00:00
abstract：:Retroviral gene marking has been used successfully in preclinical and clinical transplantation settings. Highly sensitive techniques for vector insertion-site determination, such as linear amplification-mediated polymerase chain reaction (LAM-PCR) in conjunction with next-generation sequencing, have been introduced to...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/j.exphem.2012.09.003
更新日期：2013-01-01 00:00:00
abstract：:Serum obtained from (C3H X C57BL) F1 hybrid mice injected with parental (C57BL) lymph node cells after 600 rad irradiation contained a high level of an erythropoietic factor, which enhanced erythroid colony formation by fetal C57BL liver cells in methylcellulose cultures. The serum level of this erythroid colony-stimu...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1984-11-01 00:00:00
abstract：:Cells for study were obtained from mouse bone marrow by three methods: 1) Mechanical dissociation; 2) Trypsin release; and 3) Passage through a syringe and needle. The ratio of the fibroblast colony-forming cells in these suspensions was, respectively, 1:13:1. Of the colonies formed by cells obtained by trypsin releas...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1982-02-01 00:00:00
abstract：:Fanconi anemia (FA) is a rare recessive disease characterized by progressive bone marrow failure, congenital abnormalities, and increased incidence of cancers. To date, mutations in 22 genes can cause FA or an FA-like phenotype. In China, in addition to clinical information, FA diagnosis primarily relies on genetic se...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/j.exphem.2018.07.003
更新日期：2018-10-01 00:00:00
abstract：OBJECTIVE:Recruitment of endothelial progenitor cells to the sites of ischemia has recently been suggested as a mechanism of tissue repair. Here we address the hypothesis that the hypoxia-inducible full-length endothelial-monocyte-activating polypeptide II (EMAP II) provides a mechanism to recruit late outgrowth highly...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/j.exphem.2006.05.021
更新日期：2006-08-01 00:00:00
abstract：:Despite its growing use as a marker of proliferation, the relationship between expression of the nuclear antigen Ki67 and other indices of proliferation in acute myelogenous leukemia (AML) has not been elucidated. In this study, short-term primary suspension cultures of human AML bone marrow cells were used to compare...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1993-12-01 00:00:00
abstract：:We compared the kinetic recovery of lymphocytes and their subsets in two groups of patients submitted to allogeneic peripheral blood progenitor cell transplantation (allo-PBT): those receiving lymphocyte-depleted leukaphereses by positive selection of CD34+ cells (group 1, n = 18) and those receiving unmanipulated leu...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：10.1016/s0301-472x(98)00029-0
更新日期：1999-03-01 00:00:00
abstract：:The effect of staurosporine, a novel calcium/phospholipid-dependent protein kinase (protein kinase C) inhibitor, on differentiation of human promyelocytic leukemic HL-60 cells, was investigated. Staurosporine inhibited HL-60-cell proliferation in a concentration-dependent manner, but did not induce HL-60-cell differen...
journal_title：Experimental hematology
pub_type： 杂志文章
doi：
更新日期：1988-01-01 00:00:00
