Abstract:
:Distinctive patterns of chromatin modification control gene expression and define cellular identity during development and cell differentiation. Polycomb repressive complex 2 (PRC2), the sole mammalian enzymatic complex capable of establishing gene-repressive high-degree methylation of histone H3 at lysine 27 (H3K27), plays crucial roles in regulation of normal and malignant hematopoiesis. Recently, increasing evidence has indicated that recurrent gain-of-function mutation and overexpression of EZH2, the catalytic subunit of PRC2, drive and promote malignant transformation such as B-cell lymphomagenesis, providing a rationale for PRC2 inhibition as a novel anticancer strategy. Here, we summarize the recently developed strategies for inhibition of PRC2, which include a series of highly specific, highly potent, small-molecule inhibitors of EZH2 and EZH1, an EZH2-related methyltransferase. PRC2 establishes functional crosstalk with numerous epigenetic machineries during dynamic regulation of gene transcription. Perturbation of such functional crosstalk caused by genetic events observed in various hematologic cancers, such as inactivation of SNF5 and somatic mutation of UTX, confers PRC2 dependence, thus rendering an increased sensitivity to PRC2 inhibition. We discuss our current understanding of EZH2 somatic mutations frequently found in B-cell lymphomas and recurrent mutations in various other epigenetic regulators as novel molecular predictors and determinants of PRC2 sensitivity. As recent advances have indicated a critical developmental or tumor-suppressive role for PRC2 and EZH2 in various tissue types, we discuss concerns over potentially toxic or even adverse effects associated with EZH2/1 inhibition in certain biological contexts or on cancer genetic background. Collectively, inhibition of PRC2 catalytic activity has emerged as a promising therapeutic intervention for the precise treatment of a range of genetically defined hematologic malignancies and can be potentially applied to a broader spectrum of human cancers that bear similar genetic and epigenetic characteristics.
journal_name
Exp Hematoljournal_title
Experimental hematologyauthors
Xu B,Konze KD,Jin J,Wang GGdoi
10.1016/j.exphem.2015.05.001subject
Has Abstractpub_date
2015-08-01 00:00:00pages
698-712issue
8eissn
0301-472Xissn
1873-2399pii
S0301-472X(15)00163-0journal_volume
43pub_type
杂志文章,评审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 ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2009.09.009
更新日期:2009-12-01 00:00:00
abstract:OBJECTIVE:Resveratrol (3,4',5,-trihydroxystilbene, RV), an ingredient of wine, is an inhibitor of the proliferation-linked enzyme ribonucleotide reductase (RR) and shows a broad spectrum of cytotoxic effects against human cancer cells. In order to enhance these effects, we introduced additional hydroxyl moieties into t...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2006.05.018
更新日期:2006-10-01 00:00:00
abstract::The spleen colony assay, three agar colony assays and two repopulating assays have been employed to measure the effect of single doses of adriamycin, methyl CCNU, 60CO gamma-rays, vinblastine and repeated injection of cytosine arabinoside on early haemopoietic precursors. The results show that there is no consistent c...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1978-01-01 00:00:00
abstract::Unlike cell lines, human hematopoietic stem cells (HSCs) are less efficiently transduced with HIV-1 vectors, potentially limiting this approach. To investigate which step (internalization, reverse transcription, nuclear transport, and integration) limits lentiviral transduction, we evaluated the kinetics of lentiviral...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2015.10.003
更新日期:2016-02-01 00:00:00
abstract:OBJECTIVE:Polycythemia rubra vera-1 (PRV-1) is a GPI-linked protein that is expressed on a subgroup of neutrophils. The number of PRV-1-expressing neutrophils increases in pregnancy and sepsis, or after administration of granulocyte colony-stimulating factor. Expression of the PRV-1 gene is also increased in patients w...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2007.09.008
更新日期:2007-11-01 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::More than 2million human erythroblasts extrude their nuclei every second in bone marrow under hypoxic conditions (<7% O2). Enucleation requires specific signal transduction pathways and the local assembly of contractile actomyosin rings. However, the energy source driving these events has not yet been identified. We e...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2019.02.004
更新日期:2019-04-01 00:00:00
abstract::Dendritic cells (DC) are recognized as the most potent antigen-presenting cells with the ability to stimulate naive resting T cells and to initiate primary immune responses. Encouraging results in vaccination studies in animal models and the development of protocols to generate sufficient numbers of human DC for clini...
journal_title:Experimental hematology
pub_type: 杂志文章,评审
doi:10.1016/s0301-472x(01)00730-5
更新日期:2001-11-01 00:00:00
abstract::Thrombocytopenia is an important clinical problem for many acquired immunodeficiency syndrome (AIDS) patients. Recently, the utility of recombinant cytokines in alleviating the hematopoietic complications of AIDS and AIDS therapy has been evaluated. The newly cloned cytokine stem cell factor (SCF) has been demonstrate...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1993-08-01 00:00:00
abstract::A factor present in normal mouse serum stimulates proliferation of late erythroid precursors grown in cultures in vitro. This factor was shown not to have a corrective effect on culture conditions by the following criteria: (a) CFU-E frequency in the absence of NMS was at least as great as published data for various m...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1984-08-01 00:00:00
abstract::Allogeneic bone marrow recipients exhibit a complex and multifactorial immunodeficiency affecting numerous effector functions for various periods of time. In order to evaluate their Fc-mediated monocyte-macrophage (MM) function we studied the clearance of IgG-coated Rh-positive erythrocytes (EA) in healthy control sub...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1989-10-01 00:00:00
abstract::Studies were undertaken to produce monoclonal antibodies directed against the murine receptor for macrophage colony-stimulating factor (M-CSF or CSF-1). Sprague-Dawley rats were injected with lysates prepared from a murine myelomonocytic cell line (RAW cell line) that has high levels of M-CSF receptors. Spleen cells f...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1993-04-01 00:00:00
abstract:OBJECTIVE:To investigate whether Flk1(+)CD31(-)CD34(-) cells isolated from fetal bone marrow (BM) have characteristics of hemangioblasts, i.e., progenitors of endothelial and hematopoietic cells. MATERIALS AND METHODS:Mononuclear cells from fetal BM were negatively sorted by CD45, GlyA, and CD34 micromagnetic beads, t...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(03)00087-0
更新日期:2003-07-01 00:00:00
abstract:OBJECTIVE:To evaluate feasibility, safety, and efficacy of peripheral blood stem cell collection (PBSCC) and autologous stem cell transplantation (ASCT), to treat patients diagnosed of high-risk or relapsed HIV-associated lymphoma (HIV+ Ly), responding to highly active antiretroviral therapy (HAART). METHODS:Prospecti...
journal_title:Experimental hematology
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1016/j.exphem.2004.12.008
更新日期:2005-04-01 00:00:00
abstract::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 ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2018.12.002
更新日期:2019-02-01 00:00:00
abstract::The granulocyte defects of Chediak-Higashi syndrome (CHS) include neutropenia, characteristic giant lysosomal granule morphology, and functionally abnormal cell motility, degranulation, and bacterial killing. Findings of elevated levels of adenosine 3', 5' cyclic monophosphate nucleotide (cAMP) and of concanavalin A (...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1985-02-01 00:00:00
abstract::Normal and myeloid leukemic spleen cells from RF mice were cultured in vitro in plasma clots. In situ histochemical staining and karyotypic analysis of the colonies formed in the clot revealed that the colonies produced by leukemic and normal progenitors were indistinguishable morphologically and cytochemically. Colon...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1978-02-01 00:00:00
abstract::The cloning efficiency of T-lymphocyte progenitor cells (CFU-T) is dependent on mononuclear cell concentration, with a triphasic growth curve. At low plating cell concentrations, hydrocortisone causes a dose-dependent decrease in cloning efficiency, whereas at high cell concentrations hydrocortisone causes increased c...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1989-02-01 00:00:00
abstract::The effects of chronic exposure to graded hypoxia (inspired PO2 = 146, 90, 78, 73 and 60 torr) on the development of hypoxia-induced hemoglobinemia and the rate of hemoglobin degradation in intact and acutely splenectomized rats were studied. Hemoglobin mass increased with hypoxia over the whole range studied. Hemoglo...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1980-03-01 00:00:00
abstract::Friend virus replicating target cells have been characterized by in vitro infection of bone marrow cells from DBA/2 mice after multiple injections of hydroxyurea (HU), after bleeding and/or hypertransfusion and after busulfan treatment. The concentration of CFUS, BFUE and CFUE in the cell suspension was correlated wit...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1982-05-01 00:00:00
abstract::Induced pluripotent stem cells (iPSCs) can be generated from various types of cells with transduction of defined transcription factors. Patient-derived iPSCs are becoming commonly utilized for understanding the molecular pathways involved in disease and for the development of novel targeted therapies. With the use of ...
journal_title:Experimental hematology
pub_type: 杂志文章,评审
doi:10.1016/j.exphem.2015.06.006
更新日期:2015-08-01 00:00:00
abstract::Several prospective randomized trials in acute myelocytic leukemia (AML) documented a lower relapse rate with autologous bone marrow transplantation (ABMT) than with conventional chemotherapy. However, they also identified some transplant difficulties, such as failure to collect sufficient numbers of stem cells, slow ...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(99)00121-6
更新日期:1999-12-01 00:00:00
abstract:OBJECTIVE:Umbilical cord blood (CB) provides an alternative source of hematopoietic progenitor cells for transplantation; however, prolonged thrombocytopenia remains a major obstacle due to the low numbers of megakaryocyte progenitor (Mk-prog) cells and their subsequent delayed engraftment. In this study, we improved t...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/s0301-472x(02)00884-6
更新日期:2002-09-01 00:00:00
abstract::This study evaluated the usefulness of a matrix culture system, the artificial capillary culture system, for the growth of hematopoietic cells, the maintenance of CFUS and the collection of GM-CSF. The system was compared to monolayer, gelfoam sponge and Dexter liquid cultures. Monolayer cultures of adherent lymphohem...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1981-02-01 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:Cyclosporine A (CsA), known as an effective immunosuppressive agent, is widely used in clinical fields. Mesenchymal stem cells may exert immunomodulatory effects on the immune system, but the exact mechanisms underlying them remain controversial. Here we investigated whether human adipose tissue-derived mesen...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2010.10.009
更新日期:2011-02-01 00:00:00
abstract::We performed the present study to define the in vitro hemopoietic activity of murine recombinant (r) granulocyte colony-stimulating factor (G-CSF) using murine hemopoietic culture systems of normal bone marrow cells, fetal liver cells, and spleen cells of 5-fluorouracil (FU)-treated mice. Recombinant G-CSF supported o...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1987-10-01 00:00:00
abstract::Bone marrow endothelial cells are likely to play an important role in the homing of hematopoietic progenitor cells. In view of analyzing the interactions between endothelial cells and hematopoietic progenitor cells, we studied several methods of isolating endothelial cells from human bone marrow, including fluorescenc...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1995-01-01 00:00:00
abstract:OBJECTIVE:Endothelial progenitor cells (EPCs) are used for angiogenic therapies or as biomarkers to assess cardiovascular disease risk. However, there is no uniform definition of an EPC, which confounds EPC studies. EPCs are widely described as cells that coexpress the cell-surface antigens CD34, AC133, and vascular en...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:10.1016/j.exphem.2007.04.002
更新日期:2007-07-01 00:00:00
abstract::T lymphocytes were derived by E-rosetting techniques from the peripheral blood and bone marrow of 12 healthy donors. Following incubation of 18 h with PWM, PHA, Con-A or culture medium (RPMI) alone, the lymphocytes were harvested by centrifugation and washed. Both lymphocytes and culture supernatants were tested for C...
journal_title:Experimental hematology
pub_type: 杂志文章
doi:
更新日期:1982-03-01 00:00:00