Abstract:
:The Fanconi anaemia protein FANCD2 suppresses PPARƔ to maintain haematopoietic stem cell's (HSC) function; however, the underlying mechanism is not known. Here we show that FANCD2 acts in concert with the Notch target HES1 to suppress inflammation-induced PPARƔ in HSC maintenance. Loss of HES1 exacerbates FANCD2-KO HSC defects. However, deletion of HES1 does not cause more severe inflammation-mediated HSC defects in FANCD2-KO mice, indicating that both FANCD2 and HES1 are required for limiting detrimental effects of inflammation on HSCs. Further analysis shows that both FANCD2 and HES1 are required for transcriptional repression of inflammation-activated PPARg promoter. Inflammation orchestrates an overlapping transcriptional programme in HSPCs deficient for FANCD2 and HES1, featuring upregulation of genes in fatty acid oxidation (FAO) and oxidative phosphorylation. Loss of FANCD2 or HES1 augments both basal and inflammation-primed FAO. Targeted inhibition of PPARƔ or the mitochondrial carnitine palmitoyltransferase-1 (CPT1) reduces FAO and ameliorates HSC defects in inflammation-primed HSPCs deleted for FANCD2 or HES1 or both. Finally, depletion of PPARg or CPT1 restores quiescence in these mutant HSCs under inflammatory stress. Our results suggest that this novel FANCD2/HES1/PPARƔ axis may constitute a key component of immunometabolic regulation, connecting inflammation, cellular metabolism and HSC function.
journal_name
Br J Haematoljournal_title
British journal of haematologyauthors
Wu L,Li X,Lin Q,Chowdhury F,Mazumder MH,Du Wdoi
10.1111/bjh.17230subject
Has Abstractpub_date
2020-11-22 00:00:00eissn
0007-1048issn
1365-2141pub_type
杂志文章abstract::The pyrimidine analogue cytosine arabinoside (AraC) is one of the most effective drugs used in the treatment of acute leukaemia. Overexpression of the multidrug resistance (MDR-1) gene and its product, P-glycoprotein (P-gp), is associated with cellular resistance to drugs, such as anthracyclines and vinca alkaloids. T...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2001.02979.x
更新日期:2001-09-01 00:00:00
abstract::The iron chelator deferasirox (DFX) prevents complications related to transfusional iron overload in several haematological disorders characterized by marrow failure. It is also able to induce haematological responses in a percentage of treated patients, particularly in those affected by myelodysplastic syndromes. The...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.13381
更新日期:2015-07-01 00:00:00
abstract::We describe five adult patients with sickle cell anaemia (SS) who developed clinical, radiological and histological evidence of splenic regrowth while receiving regular blood transfusions. Five patients, all homozygous SS, range 23-34 years, were commenced on hypertransfusion therapy. Three patients were transfused be...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.d01-1974.x
更新日期:1997-01-01 00:00:00
abstract::To identify and treat patients at high risk of cytomegalovirus (CMV) pneumonia after bone marrow transplantation (BMT), we tested for CMV viraemia weekly, and performed broncho-alveolar lavage (BAL) on day 35 post-transplant in 63 recipients. 36 allogeneic BMT recipients were at a high risk of CMV pneumonia (25 CMV-se...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.1752987.x
更新日期:1997-07-01 00:00:00
abstract::Plasma iron turnover (PIT) and ferritin synthesis in the liver and spleen were studied in rats within the first 24 h of inflammation produced by turpentine injection. Comparison of the sequential changes in PIT and ferritin synthesis showed that alterations in ferritin synthesis preceded the changes in plasma iron exc...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:
更新日期:1977-09-01 00:00:00
abstract::We describe two patients with acute myeloid leukaemia (AML) associated with erythrophagocytosis and a pericentric inversion of chromosome 8, inv(8)(p11q13). The haematological features were indistinguishable from those of patients with the t(8;16) syndrome and its variants. Our observations emphasize the importance of...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.00587.x
更新日期:1998-03-01 00:00:00
abstract::Sickle cell anaemia is a severe inherited blood disorder for which there is presently no curative therapy other than allogeneic haematopoietic stem cell (HSC) transplantation. This therapeutic option, however, is not available to most patients because of the lack of a matched related donor. Different genetic strategie...
journal_title:British journal of haematology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2141.2011.08773.x
更新日期:2011-09-01 00:00:00
abstract::Children with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of surv...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.12348
更新日期:2013-07-01 00:00:00
abstract::In the last few years, mutations that cause disease through increased efficiency of mRNA translation have been discovered. Hereditary hyperferritinaemia-cataract syndrome (HHCS) arises from various point mutations or deletions within the iron-responsive element (IRE) in the 5'-UTR of the L-ferritin mRNA. Each unique m...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.0007-1048.2001.03310.x
更新日期:2002-03-01 00:00:00
abstract::A female patient with delayed haemolytic transfusion reaction due to anti-M antibody is described. Diagnosis was based on laboratory evidence of haemolysis and on characteristic serological findings. Anti-M was detected in the recipient's serum 7 d after the last transfusion episode. This alloantibody had not been pre...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.00970.x
更新日期:1998-10-01 00:00:00
abstract::A novel colony stimulating factor-1 (CSF-1) binding factor present in the serum from a patient in remission from lymphoma is described. Radioimmunoassay (RIA) repeatedly failed to detect circulating levels of CSF-1 in the peripheral blood system of this patient. Molecular analysis showed a normal CSF-1 gene structure ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1995.tb08937.x
更新日期:1995-01-01 00:00:00
abstract::The growth of marrow fibroblasts from patients with myeloproliferative disorders (MPD) was investigated using platelet derived growth factor (PDGF) and human serum as mitogens in the presence of human plasma derived serum. The proliferation of fibroblasts in MPD patients was increased compared to normal individuals, e...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1988.tb07616.x
更新日期:1988-06-01 00:00:00
abstract::A mechanism has been proposed in which nitric oxide (NO) may bind to cysteine beta93 and be transported by haemoglobin from the lungs to the tissues and modify vascular tone. In addition, it has been reported that treatment of sickle cell anaemia blood with 80 p.p.m. NO gas in air shifts the oxygen affinity, as measur...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.02203.x
更新日期:2000-08-01 00:00:00
abstract::Pituitary tumour transforming gene (PTTG) isolated from pituitary tumour cells transforms cells in vitro and causes in vivo tumour formation. PTTG is expressed in several human tumours and cell lines. In normal adult tissues, the testis expresses abundant levels of PTTG mRNA comparable to that found in tumour cells. A...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2002.03941.x
更新日期:2002-12-01 00:00:00
abstract::A number of disorders cause iron overload: some are of genetic origin, such as hereditary haemochromatosis, while others are acquired, for instance due to repeated transfusions. This article reviews the treatment options for hereditary haemochromatosis, with special attention to the use of erythrocytapheresis. In gene...
journal_title:British journal of haematology
pub_type: 杂志文章,评审
doi:10.1111/bjh.14376
更新日期:2016-12-01 00:00:00
abstract::Coagulation activity and whole-blood viscosity were measured in the steady state, and serially during painful crisis, in eight patients with sickle-cell anaemia. Platelet and coagulation activation occurred in the steady state and became more pronounced early in crisis. Whole-blood viscosity increased during crisis in...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1979.tb03685.x
更新日期:1979-01-01 00:00:00
abstract::The contribution of red cell size (mean cell volume) to the clinical and haematological manifestations of homozygous sickle cell (SS) disease has been investigated by comparing the features of two groups of patients with low (less than or equal to 80 fl) and high (greater than 95 fl) MCV values after matching for age,...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1981.tb02736.x
更新日期:1981-07-01 00:00:00
abstract::Very Late Antigen-4 (VLA-4, α4β1-integrin, ITGA4) orchestrates cell-cell and cell-endothelium adhesion. Given the proposed role of VLA-4 in sickle cell disease (SCD) pathophysiology, we evaluated the ability of the VLA-4 blocking antibody natalizumab to inhibit SCD blood cell adhesion. Natalizumab recognized surface V...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.14158
更新日期:2016-09-01 00:00:00
abstract::An immunotoxin containing an anti-CD30 monoclonal antibody (Ber-H2) and saporin, a ribosome-inactivating protein type 1, is described. It specifically inhibits protein synthesis by Hodgkin derived target cell lines with a very high efficiency (IC50 ranging from 5 x 10(-12) M to 5 x 10(-14) M, as saporin), while irrele...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1992.tb08208.x
更新日期:1992-06-01 00:00:00
abstract::This case study provides evidence for clonal evolution in pre-B-cell leukaemia. At diagnosis, the lymphoblasts from a 3-year-old boy were morphologically subtyped as L1 (French-American-British classification). Their immunophenotype was CALLA+, CIgM+, SIg-, TdT+, and the karyotype was pseudodiploid with a 1;19 translo...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1984.tb03971.x
更新日期:1984-03-01 00:00:00
abstract::Fetal haemoglobin levels have been measured prospectively in 135 autopsy cases of sudden, unexpected infant deaths (31 pre-term, 104 full term) using standard laboratory methods. These results have been compared with Hb F values from a normal control group of 570 living infants (145 pre-term, 425 full-term) with a pos...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1992.tb06440.x
更新日期:1992-10-01 00:00:00
abstract::Recent findings have indicated the importance of factor V (FV) in causing resistance to activated protein C (APC) in a high proportion of patients with venous thrombosis. This prompted us to investigate whether resistance could be due to defective inactivation of FVa by APC. Consequently, we amplified a 3.2 kb fragmen...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb05005.x
更新日期:1994-09-01 00:00:00
abstract::The myelodysplastic syndromes (MDS) display both haematological and biological heterogeneity with variable leukaemia potential. MicroRNAs play an important role in tumour suppression and the regulation of self-renewal and differentiation of haematopoietic progenitors. Using a microarray platform, we evaluated microRNA...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2011.08581.x
更新日期:2011-04-01 00:00:00
abstract::Adhesive interactions between haemopoietic progenitor cells and bone marrow sinusoidal endothelium are potentially important in the homing of these cells back to the extravascular compartment of the marrow to re-establish haemopoiesis following stem cell transplantation. A simple method for the isolation and culture o...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb05128.x
更新日期:1994-12-01 00:00:00
abstract::We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnos...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.14260
更新日期:2016-11-01 00:00:00
abstract::Treatment-free remission (TFR) has recently emerged as a goal of treatment in chronic myeloid leukaemia (CML). Molecular remission is sustained in around 30% of imatinib-treated patients who stop treatment after ≥2 years with undetectable minimal residual disease (UMRD) by conventional real-time reverse transcription ...
journal_title:British journal of haematology
pub_type: 杂志文章,评审
doi:10.1111/bjh.12892
更新日期:2014-07-01 00:00:00
abstract::The addition of radioimmunotherapy to conventional and reduced-intensity conditioning has been shown to be feasible and effective. Within an ongoing prospective phase II trial, 22 patients with advanced myeloid malignancies and a median age of 65 years (range 54-76) received anti-CD66 Rhenium radioimmunotherapy follow...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2009.08025.x
更新日期:2010-03-01 00:00:00
abstract::This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β-thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase-3...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.12076
更新日期:2013-02-01 00:00:00
abstract::Atrial fibrillation (AF) is a common cardiac arrhythmia with a 5-20% annual risk of stroke. Warfarin reduces this risk by at least 60%. Despite adequate anticoagulation within the target International Normalized Ratio (INR) range of 2.0-3.0, some patients still experience thrombotic and bleeding events. It is now poss...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2008.07279.x
更新日期:2008-09-01 00:00:00
abstract::Accurate clinical staging is crucial for adequate risk-adapted treatment in Hodgkin lymphoma (HL) to prevent patients from under- or over-treatment. Within the latest German Hodgkin Study Group trial generation, diagnostic findings such as histopathology, computerized tomography imaging and clinical risk factors were ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.13646
更新日期:2015-11-01 00:00:00