1: 清华大学陈晔光
Blood. 2006 Oct 10; [Epub ahead of print]
MCP-1 mediates TGF-{beta}-induced angiogenesis by stimulating vascular smooth
muscle cell migration.
Ma J, Wang Q, Fei T, Han JD, Chen YG.
State Key Lab. of Biomembrane and Membrane Biotechnology, Department of
Biological Sciences and Biotechnology, Tsinghua University, Beijing, China.
Transforming growth factor-beta (TGF-beta) and its signaling mediators play
crucial roles in vascular formation. Our previous microarray analysis has
identified monocyte chemoattractant protein-1 (MCP-1) as a TGF-beta target gene
in endothelial cells (ECs). Here, we report that MCP-1 mediates the angiogenic
effect of TGF-beta by recruiting vascular smooth muscle cells (VSMCs) and
mesenchymal cells towards ECs. By employing chick chorioallantoic membrane
assay, we showed that TGF-beta promotes the formation of new blood vessels and
this promotion is attenuated when MCP-1 activity is blocked by its neutralizing
antibody. Wound healing and transwell assays established that MCP-1 functions as
a chemoattractant to stimulate migration of VSMCs and mesenchymal 10T1/2 cells
toward ECs. Furthermore, the conditioned media from TGF-beta-treated ECs
stimulate VSMC migration, and inhibition of MCP-1 activity attenuates
TGF-beta-induced VSMC migration toward ECs. Finally, we found that MCP-1 is a
direct gene target of TGF-beta via Smad3/4. Taken together, our findings suggest
that MCP-1 mediates TGF-beta-stimulated angiogenesis by enhancing migration of
mural cells towards ECs and thus promoting the maturation of new blood vessels.
PMID: 17032917 [PubMed - as supplied by publisher]
2: 瑞金陈赛娟，陈竺
Blood. 2006 Sep 21; [Epub ahead of print]
Aberrant transcriptional regulation of the MLL fusion partner EEN gene by
AML1-ETO and its implication in leukemogenesis.
Ma LH, Liu H, Xiong H, Chen B, Zhang XW, Wang YY, Le HY, Huang QH, Zhang QH, Li
BL, Chen Z, Chen SJ.
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology,
Shanghai, China.
EEN (extra eleven nineteen) gene located on chromosome 19p13 was cloned as a
fusion with MLL from an acute myeloid leukemia (AML) patient with translocation
t(11;19)(q23;p13). In this study, we characterized the genomic structure of EEN
gene including its 5' regulatory region and transcription start site (TSS). We
found that Sp1 could bind to the GC-stretch of EEN promoter and was critical for
the normal EEN expression, while the leukemia associated fusion protein AML1-ETO
could aberrantly transactivate EEN gene through an AML1 binding site. Of note,
overexpressed EEN showed oncogenic properties, such as transforming potential in
NIH3T3 cells, stimulating cell proliferation and increasing the activity of
transcriptional factor AP-1. Retroviral transduction of EEN increased
self-renewal and proliferation of murine hematopoietic progenitor cells.
Moreover, Kasumi-1 and HL60 cell growth was inhibited with down regulation of
EEN by RNAi. These findings demonstrate that EEN might be a common target in two
major types of AML associated with MLL or AML1 translocations, and
over-expression of EEN may play an essential role in leukemogenesis.
PMID: 16990610 [PubMed - as supplied by publisher]
3: 吉林大学生科院赵志壮
Blood. 2006 Aug 31; [Epub ahead of print]
JAK2V617F: Prevalence in a large Chinese hospital population.
Xu X, Zhang Q, Luo J, Xing S, Li Q, Krantz SB, Fu X, Zhao ZJ.
Edmond H. Fischer Signal Transduction Laboratory, College of Life Sciences,
Jilin University, China.
Recently, the JAK2 V617F mutation was found in patients with myeloproliferative
disorders (MPDs) including most with polycythemia vera (PV). The mutant JAK2 has
increased kinase activity, and it was shown to be pathogenic in mouse models.
Herein we analyzed blood samples randomly collected from a clinical laboratory.
Surprisingly, as many as 37 samples out of a total of 3935 were found positive
for the JAK2 mutation. However, only one of these samples had blood test results
indicative for probable PV, but several had non-hematological diseases. On
average, samples with the mutation had normal red cell counts but significantly
higher white blood cell and platelet counts although most were within the normal
range. The data suggest that the JAK2 V617F mutation is apparently much more
common than MPDs. Its occurrence may be a prelude to full blood cell
abnormalities and other diseases, but it cannot by itself diagnose MPDs.
PMID: 16946305 [PubMed - as supplied by publisher]
4: 二军大曹雪涛
Blood. 2006 Oct 15;108(8):2678-86. Epub 2006 Jun 22.
DIgR2, dendritic cell-derived immunoglobulin receptor 2, is one representative
of a family of IgSF inhibitory receptors and mediates negative regulation of
dendritic cell-initiated antigen-specific T-cell responses.
Shi L, Luo K, Xia D, Chen T, Chen G, Jiang Y, Li N, Cao X.
Institute of Immunology and State Key Laboratory of Medical Immunology, Second
Military Medical University, 800 Xiangyin Rd, Shanghai 200433, PR China; email:
caoxt@public3.sta.net.cn.
Dendritic cells (DCs) are specialized antigen-presenting cells that play crucial
roles in the initiation and regulation of immune responses. Maturation and
activation of DCs are controlled by a balance of the inhibitory and activating
signals transduced through distinct surface receptors. Many inhibitory receptors
expressed by DCs have been identified, whereas the new members and their
functions need further investigation. In this study, we functionally
characterized DC-derived immunoglobulin receptor 2 (DIgR2) as a novel
representative of a family of inhibitory receptors belonging to the
immunoglobulin superfamily. We show that DIgR2 contains 2 immunoreceptor
tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic region and that
DIgR2 associates with Src homology-2 domain-containing protein tyrosine
phosphatases-1 (SHP-1). Blockade of DIgR2 on DCs by pretreatment with DIgR2-Ig
fusion protein or by silencing with specific small interfering RNA enhances
DC-initiated T-cell proliferation and antigen-specific T-cell responses both in
vitro and in vivo. Furthermore, immunization of mice with antigen-pulsed,
DIgR2-silenced DCs elicits more potent antigen-specific CD4(+) and CD8(+) T-cell
responses, thus protecting the vaccinated mice from tumor challenge more
effectively. Our data suggest that DIgR2 is a functionally inhibitory receptor
and can mediate negative signaling to regulate DC-initiated antigen-specific
T-cell responses.
PMID: 16794255 [PubMed - in process]
5: 二军大曹雪涛
Blood. 2006 Oct 1;108(7):2307-15. Epub 2006 Jun 15.
TLR agonists promote ERK-mediated preferential IL-10 production of regulatory
dendritic cells (diffDCs), leading to NK-cell activation.
Qian C, Jiang X, An H, Yu Y, Guo Z, Liu S, Xu H, Cao X.
Institute of Immunology and National Key Laboratory of Medical Immunology,
Second Military Medical University, 800 Xiangyin Rd, Shanghai, 200433, People's
Republic of China.
Regulatory dendritic cells (DCs) play an important role in maintaining
peripheral tolerance or immune homeostasis. Our previous study demonstrated that
mature DCs could be driven by splenic stroma to proliferate and differentiate
into a novel subset of regulatory DCs (diffDCs) displaying a Th2-biased cytokine
profile. However, the underlying mechanisms for the unique cytokine profile of
diffDCs and how diffDCs regulate the innate and adaptive immunity in response to
toll-like receptor (TLR) agonists remain unclear. Here, we report that unlike
immature DCs, diffDCs secrete more interleukin 10 (IL-10) but little IL-12p70 in
response to lipopolysaccharide (LPS) or other TLR agonists. Up-regulation of
extracellular signal-regulated kinase (ERK1/2) activation was shown to be
responsible for IL-10 preferential production, and suppression of p38 activation
was for impaired IL-12p70 production in diffDCs. Interestingly, LPS treatment
could not reverse the inhibitory effect of diffDCs on the proliferation of
antigen-specific CD4+ T cells. However, diffDCs could activate natural killer
(NK) cells through diffDC-derived IL-10, and even more markedly after
stimulation of TLR agonists. These diffDC-activated NK cells could in turn kill
surrounding diffDCs. Our results illuminate signal pathways for the unique
cytokine profile of diffDCs, and diffDCs can exert their regulatory function
even after inflammatory stimuli, thus reflecting one way for strict regulation
of immune response.
PMID: 16778140 [PubMed - in process]
6:浙大曹雪涛
Blood. 2006 Aug 15;108(4):1189-97. Epub 2006 Apr 20.
Endothelial stroma programs hematopoietic stem cells to differentiate into
regulatory dendritic cells through IL-10.
Tang H, Guo Z, Zhang M, Wang J, Chen G, Cao X.
Institute of Immunology, Zhejian University, Hangzhou, PR China.
Regulatory dendritic cells (DCs) have been reported recently, but their origin
is poorly understood. Our previous study demonstrated that splenic stroma can
drive mature DCs to proliferate and differentiate into regulatory DCs, and their
natural counterpart with similar regulatory function in normal spleens has been
identified. Considering that the spleen microenvironment supports hematopoiesis
and that hematopoietic stem cells (HSCs) are found in spleens of adult mice, we
wondered whether splenic microenvironment could differentiate HSCs into
regulatory DCs. In this report, we demonstrate that endothelial splenic stroma
induce HSCs to differentiate into a distinct regulatory DC subset with high
expression of CD11b but low expression of Ia. CD11b(hi)Ia(lo) DCs secreting high
levels of TGF-beta, IL-10, and NO can suppress T-cell proliferation both in
vitro and in vivo. Furthermore, CD11b(hi)Ia(lo) DCs have the ability to potently
suppress allo-DTH in vivo, indicating their preventive or therapeutic
perspectives for some immunologic disorders. The inhibitory function of
CD11b(hi)Ia(lo) DCs is mediated through NO but not through induction of
regulatory T (Treg) cells or T-cell anergy. IL-10, which is secreted by
endothelial splenic stroma, plays a critical role in the differentiation of the
regulatory CD11b(hi)Ia(lo) DCs from HSCs. These results suggest that splenic
microenvironment may physiologically induce regulatory DC differentiation in
situ.
PMID: 16627758 [PubMed - indexed for MEDLINE]
7:南京大学医药技术重点实验室王德民
Blood. 2006 Jul 15;108(2):566-74. Epub 2006 Mar 28.
Proteasome-dependent down-regulation of activated Stat5A in the nucleus.
Chen Y, Dai X, Haas AL, Wen R, Wang D.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China.
A broad spectrum of cytokines can activate the signal transducer and activator
of transcription 5 (Stat5) by inducing a single tyrosine phosphorylation of the
molecule. Although the process of Stat5 activation has been well studied, the
mechanism by which it is inactivated is not fully understood. We demonstrate
that the proteasome inhibitor MG132, but not the nuclear export inhibitor
leptomycin B (LMB), stabilizes active nuclear Stat5A, whereas MG132 only
partially stabilizes active cytoplasmic Stat5A. Importantly, ubiquitinated
Stat5A is detected in the nucleus and the polyubiquitination of active Stat5A is
K48 linked, a linkage type targeting proteins for degradation. Ubiquitination of
Stat5A is recapitulated in a cell-free system, and Ubc5 is identified as the
E2-conjugating enzyme for Stat5A ubiquitination. Interestingly, phosphorylation
of Stat5A per se is not required for ubiquitination. Finally, C-terminal
deletion analysis of Stat5A localizes the amphipathic region of amino acids
751-762 as a ubiquitination signal, possibly representing an E3 recognition
motif. Taken together, these results demonstrate that the down-regulation of
nuclear and cytoplasmic active Stat5A is differentially regulated. In the
nucleus, ubiquitin/proteasome-mediated protein degradation is the dominant
mechanism for the down-regulation of active Stat5A, whereas in the cytoplasm,
protein tyrosine phasphatase is a major player in the down-regulation of active
Stat5A.
PMID: 16569768 [PubMed - indexed for MEDLINE]
8: 清华大学罗永章
Blood. 2006 May 1;107(9):3564-71. Epub 2006 Jan 10.
The angiogenic function of nucleolin is mediated by vascular endothelial growth
factor and nonmuscle myosin.
Huang Y, Shi H, Zhou H, Song X, Yuan S, Luo Y.
Laboratory of Protein Chemistry, Department of Biological Sciences and
Biotechnology, Tsinghua University, Beijing 100084, PR China.
Nucleolin, originally described as a nuclear protein, was recently found to be
expressed on the surface of endothelial cells during angiogenic. However, the
functions of cell-surface nucleolin in angiogenic remain mysterious. Here we
report that upon endothelial cells adhering to extracellular matrix components,
vascular endothelial growth factor (VEGF) mobilizes nucleolin from nucleus to
cell surface. Functional blockage or down-regulation of the expression of
cell-surface nucleolin in endothelial cells significantly inhibits the migration
of endothelial cells and prevents capillary-tubule formation. Moreover,
nonmuscle myosin heavy chain 9 (MyH9), an actin-based motor protein, is
identified as a nucleolin-binding protein. Subsequent studies reveal that MyH9
serves as a physical linker between nucleolin and cytoskeleton, thus modulating
the translocation of nucleolin. Knocking down endogenous MyH9, specifically
inhibiting myosin activity, or overexpressing functional deficient MyH9 disrupts
the organization of cell-surface nucleolin and inhibits its angiogenic function.
These studies indicate that VEGF, extracellular matrix, and intracellular motor
protein MyH9 are all essential for the novel function of nucleolin in
angiogenic.
PMID: 16403913 [PubMed - indexed for MEDLINE]
9: 北医人民医院血研所
Blood. 2006 Apr 15;107(8):3065-73. Epub 2005 Dec 27.
Conditioning including antithymocyte globulin followed by unmanipulated
HLA-mismatched/haploidentical blood and marrow transplantation can achieve
comparable outcomes with HLA-identical sibling transplantation.
Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W, Chen H, Liu DH, Gao ZY, Chen YH,
Xu LP, Zhang YC, Ren HY, Li D, Liu KY.
Peking University Institute of Hematology, 11 Xizhimen South Street, Beijing
100044, China.
lscm2@yahoo.comThe outcomes of 293 patients with leukemia undergoing HLA-identical sibling (n =
158) or related HLA-mismatched (n = 135) hematopoietic cell transplantation
(HCT) performed during the same time period were compared. Patients received
BUCY2 in HLA-identical sibling HCT or BUCY2 + ATG in mismatched HCT as
conditioning regimens, followed by unmanipulated marrow and/or peripheral blood
(PB) transplantation. All patients achieved full engraftment. The cumulative
incidences of grades II to IV acute graft-versus-host disease (aGVHD) in the
matched and mismatched cohorts were 32% (CI, 25%-39%) versus 40% (CI, 32%-48%, P
= .13), respectively, with the relative risk (RR) = 0.64 (95% CI, 0.43-0.94), P
= .02. The incidence of chronic GVHD did not differ significantly between the
cohorts (P = .97). Two-year incidences of treatment-related mortality and
relapse for matched versus mismatched were 14% (range, 9%-20%) versus 22%
(range, 15%-29%) with P = .10 and 13% (range, 8%-19%) versus 18% (range,
10%-27%) with P = .40, respectively. Two-year adjusted leukemia-free survival
(LFS) and overall survival were 71% (range, 63%-78%) versus 64% (range, 54%-73%)
with P = .27 and 72% (range, 64%-79%) versus 71% (range, 62%-77%) with P = .72,
respectively. Multivariate analyses showed that only advanced disease stage and
a diagnosis of acute leukemia had increased risk of relapse, treatment failure,
and overall mortality. In summary, HCT performed with related HLA-mismatched
donors is a feasible approach with acceptable outcomes.
PMID: 16380454 [PubMed - indexed for MEDLINE]
10: 清华大学陈晔光
Blood. 2006 Mar 1;107(5):1951-4. Epub 2005 Nov 10.
Functional analysis of mutations in the kinase domain of the TGF-beta receptor
ALK1 reveals different mechanisms for induction of hereditary hemorrhagic
telangiectasia.
Gu Y, Jin P, Zhang L, Zhao X, Gao X, Ning Y, Meng A, Chen YG.
State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of
Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084,
China.
Genetic studies in mouse and zebrafish have established the importance of
activin receptor-like kinase 1 (ALK1) in formation and remodeling of blood
vessels. Single-allele mutations in the ALK1 gene have been linked to the human
type 2 hereditary hemorrhagic telangiectasia (HHT2). However, how these ALK1
mutations contribute to this disorder remains unclear. To explore the mechanism
underlying effect of the HHT-related ALK1 mutations on receptor activity, we
generated 11 such mutants and investigated their signaling activities using
reporter assay in mammalian cells and examined their effect on zebrafish
embryogenesis. Here we show that some of the HHT2-related mutations generate a
dominant-negative effect whereas the others give rise to a null phenotype via
loss of protein expression or receptor activity. These data indicate that
loss-of-function mutations in a single allele of the ALK1 locus are sufficient
to contribute to defects in maintaining endothelial integrity.
PMID: 16282348 [PubMed - indexed for MEDLINE]
11: 瑞金陈竺，陈赛娟
Blood. 2006 Feb 15;107(4):1582-90. Epub 2005 Oct 25.
Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated
apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid
leukemia.
Du Y, Wang K, Fang H, Li J, Xiao D, Zheng P, Chen Y, Fan H, Pan X, Zhao C, Zhang
Q, Imbeaud S, Graudens E, Eveno E, Auffray C, Chen S, Chen Z, Zhang J.
State Key Laboratory of Medical Genomics and Shanghai Institute of Ruijin
Hospital, School of Medicine of Shanghai Jiao Tong University, Shanghai 200025,
China.
A treatment strategy that combines arsenic trioxide (ATO) with the tyrosine
kinase inhibitor imatinib mesylate (STI571, Gleevec) appears to induce markedly
more cell apoptosis than imatinib mesylate alone in chronic myeloid leukemia
(CML). To understand the mechanisms underlying the synergistic/additive action
of these agents, we applied cDNA microarrays, component plane presentation
integrated self-organizing map (CPP-SOM), and methods of protein biochemistry to
study cell apoptosis induced by imatinib mesylate, ATO, and the combination of
the 2 agents in the CML cell line K562. Numerous features with temporospatial
relationships were revealed, indicating the coordinated regulation of molecular
networks from various aspects of proapoptotic and apoptotic activities in CML.
Imatinib mesylate appears to induce mainly the intrinsic pathway of cell
apoptosis, whereas ATO induces the endoplasmic reticulum (ER) stress-mediated
pathway of cell apoptosis, and the combination of the 2 agents seems to more
effectively induce the intrinsic, extrinsic, and ER stress-mediated pathways of
cell apoptosis, which results in a more effective and efficient induction of
programmed cell death in K562 cells. This finding appears to be supported also
by data derived from bone marrow cells of 2 patients with CML, one in chronic
phase and the other in blast-crisis phase of the disease.
PMID: 16249384 [PubMed - indexed for MEDLINE]
12: 中科院生物物理所范祖森
Blood. 2006 Feb 15;107(4):1342-51. Epub 2005 Oct 13.
NK-cell activation by LIGHT triggers tumor-specific CD8+ T-cell immunity to
reject established tumors.
Fan Z, Yu P, Wang Y, Wang Y, Fu ML, Liu W, Sun Y, Fu YX.
National Laboratory of Biomacromolecules and Center for Infection and Immunity,
Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Rd, Chaoyang
District, Beijing 100101, China.
fanz@moon.ibp.ac.cnNatural killer (NK) cells are generally reported as innate effector cells for
killing virally infected and transformed cells. It is unclear how NK cells evoke
adaptive immunity to eradicate tumors. We now demonstrate that the TNF
superfamily member, LIGHT, known as TNFSF14 and a T-cell costimulatory molecule,
is a critical ligand for the activation of NK cells. Herpesvirus entry mediator
(HVEM) is expressed on NK cells, and its engagement with LIGHT mediates NK-cell
activation. The expression of LIGHT inside tumors leads to rapid rejection in a
NK-dependent manner. Both NK and CD8+ cells are essential but not sufficient for
the rejection of tumors because mice lacking either population fail to reject
the tumor. Interestingly, activated NK cells do not kill tumors directly but can
facilitate the priming of tumor-specific CD8+ T cells in an IFN-gamma-dependent
manner. Conversely, intratumor depletion of either NK cells or IFN-gamma during
tumor progression disrupts CD8+ cell-mediated tumor rejection, suggesting that
the tumor is the essential site for the crosstalk between NK and CD8+ cells.
Furthermore, IFNG-deficient NK cells fail to effectively activate CD8+ T cells,
suggesting IFN-gamma plays an important role in NK-mediated activation of
cytotoxic T lymphocytes (CTLs). Our findings establish a direct role for LIGHT
in NK activation/expansion and a critical helper role of activated NK cells in
priming CD8+ T cells and breaking T-cell tolerance at the tumor site.
PMID: 16223768 [PubMed - indexed for MEDLINE]
13: 瑞金陈国强
Blood. 2006 Jan 15;107(2):698-707. Epub 2005 Sep 15.
Induction of tumor arrest and differentiation with prolonged survival by
intermittent hypoxia in a mouse model of acute myeloid leukemia.
Liu W, Guo M, Xu YB, Li D, Zhou ZN, Wu YL, Chen Z, Kogan SC, Chen GQ.
Department of Pathophysiology, Key Laboratory of Cell Differentiation and
Apoptosis of Ministry of Education of China, Rui-Jin Hospital, Shanghai
Jiao-Tong University School of Medicine.
We showed previously that mild real hypoxia and hypoxia-mimetic agents induced
in vitro cell differentiation of acute myeloid leukemia (AML). We here
investigate the in vivo effects of intermittent hypoxia on syngenic grafts of
leukemic blasts in a PML-RARalpha transgenic mouse model of AML. For
intermittent hypoxia, leukemic mice were housed in a hypoxia chamber equivalent
to an altitude of 6000 m for 18 hours every consecutive day. The results show
that intermittent hypoxia significantly prolongs the survival of the leukemic
mice that received transplants, although it fails to cure the disease. By
histologic and cytologic analyses, intermittent hypoxia is shown to inhibit the
infiltration of leukemic blasts in peripheral blood, bone marrow, spleen, and
liver without apoptosis induction. More intriguingly, intermittent hypoxia also
induces leukemic cells to undergo differentiation with progressive increase of
hypoxia-inducible factor-1alpha protein, as evidenced by morphologic criteria of
maturating myeloid cells and increased expression of mouse myeloid cell
differentiation-related antigens Gr-1 and Mac-1. Taken together, this study
represents the first attempt to characterize the in vivo effects of hypoxia on
an AML mouse model. Additional investigations may uncover ways to mimic the
differentiative effects of hypoxia in a manner that will benefit human patients
with AML.
PMID: 16166593 [PubMed - indexed for MEDLINE]
