Abstract:
BACKGROUND:Chimeric oncogenes encoding constitutively active protein tyrosine kinases are associated with chronic myeloid neoplasms. TEL-PDGFRbeta (TPbeta, also called ETV6-PDGFRB) is a hybrid protein produced by the t(5;12) translocation, FIP1L1-PDGFRalpha (FPalpha) results from a deletion on chromosome 4q12 and ZNF198-FGFR1 is created by the t(8;13) translocation. These fusion proteins are found in patients with myeloid neoplasms associated with eosinophilia. Wild-type receptor tyrosine kinases are efficiently targeted for degradation upon activation, in a process that requires Cbl-mediated monoubiquitination of receptor lysines. Since protein degradation pathways have been identified as useful targets for cancer therapy, the aim of this study was to compare the degradation of hybrid and wild-type receptor tyrosine kinases. DESIGN AND METHODS:We used Ba/F3 as a model cell line, as well as leukocytes from two patients, to analyze hybrid protein degradation. RESULTS:In contrast to the corresponding wild-type receptors, which are quickly degraded upon activation, we observed that TPbeta, FPalpha and the ZNF198-FGFR1 hybrids escaped down-regulation in Ba/F3 cells. The high stability of TPbeta and FPalpha hybrid proteins was confirmed in leukocytes from leukemia patients. Ubiquitination of TPbeta and FPalpha was much reduced compared to that of wild-type receptors, despite marked Cbl phosphorylation in cells expressing hybrid receptors. The fusion of a destabilizing domain to TPbeta induced protein degradation. Instability was reverted by adding the destabilizing domain ligand, Shield1. The destabilization of this modified TPbeta reduced cell transformation and STAT5 activation. CONCLUSIONS:We have shown that chimeric receptor tyrosine kinases escape ubiquitination and down-regulation and that their stabilization is critical to efficient stimulation of cell proliferation.
journal_name
Haematologicajournal_title
Haematologicaauthors
Toffalini F,Kallin A,Vandenberghe P,Pierre P,Michaux L,Cools J,Demoulin JBdoi
10.3324/haematol.2008.001149subject
Has Abstractpub_date
2009-08-01 00:00:00pages
1085-93issue
8eissn
0390-6078issn
1592-8721pii
94/8/1085journal_volume
94pub_type
杂志文章相关文献
HAEMATOLOGICA文献大全abstract::Eleven patients with advanced APL were treated with ATO (0.15 mg/Kg daily). Eight (73%) achieved molecular CR, but 5 relapsed, 1 died in molecular CR, 1 was lost to follow-up and 1 is still alive in CR after allogeneic transplantation. We suggest that ATO may be effective also in advanced APL, but given the short CR, ...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2004-05-01 00:00:00
abstract::We report the findings of the immunophenotypic profile of three cases of nasal T/NK cell lymphoma in leukemic phase. Flow cytometry analysis was carried out using cell suspensions of tumor nasal biopsies and peripheral blood. Tumor samples were composed by a mixture of a predominant subset of medium-size true NK cytCD...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.10654
更新日期:2007-02-01 00:00:00
abstract::Translocation t(9;14)(p13;q32) involving PAX5 and IGH genes was first described in lymphoplasmacytic lymphoma. New data suggest that this translocation is not restricted to a specific morphologic subtype but occurs in other B-cell lymphomas. We present three cases with a diagnosis of splenic marginal zone lymphoma and...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2006-09-01 00:00:00
abstract::Over the past 20 years we have studied 1781 patients with beta-thalassemia syndromes of which 1481 Yugoslav, 166 Bulgarian, 102 Turkish and 32 Albanian. In this paper we summarize the data on the heterogeneity and molecular basis of beta-thal, delta beta-thal and Lepore hemoglobinopathy in these four nationalities liv...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1990-09-01 00:00:00
abstract::Three cases of hepatic and/or splenic mycosis in children with acute leukemia are reported. Patients presented with fever not responding to broad spectrum antibiotics during or after prolonged and profound neutropenia. Noteworthy, in 1 case no abnormality in liver function tests was detectable at diagnosis. CT scan sh...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1991-07-01 00:00:00
abstract::We sought to confirm the prognostic importance of simple clinically available biomarkers of C-reactive protein, serum albumin, and ferritin prior to allogeneic hematopoietic cell transplantation. The study population consisted of 784 adults with acute myeloid leukemia in remission or myelodysplastic syndromes undergoi...
journal_title:Haematologica
pub_type: 杂志文章,多中心研究
doi:10.3324/haematol.2016.145847
更新日期:2016-11-01 00:00:00
abstract::Our objectives were to evaluate thrombotic complications in patients with lupus anticoagulant fulfilling Sapporo criteria, anticoagulated with an intended INR 2.0-3.0 due to venous and arterial thrombosis. In our series standard anticoagulation was safe and efficacious in preventing recurrences in patients with system...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2004-04-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Storage pool diseases (SPD) are heterogeneous disorders associated with an abnormal presence of intraplatelet granules, which cause mild to moderate bleeding diathesis. We investigated signaling through tyrosine phosphorylation of proteins occurring in platelets with total or partial absence o...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2002-06-01 00:00:00
abstract::Autoimmune lymphoproliferative syndrome is a rare genetic disorder characterized by defective FAS-mediated apoptosis, autoimmune disease, accumulation of mature T-cell receptor alpha/beta positive, CD4 and CD8 double-negative T cells and increased risk of lymphoma. Despite frequent hematologic abnormalities, literatur...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2015.138081
更新日期:2017-02-01 00:00:00
abstract::We report on five Caucasian patients with congenital polycythemia and mutations of the von Hipple-Lindau (VHL) gene: a compound heterozygote for the novel exon 1 (VHL 235C->T) and previously reported VHL 562C->G mutations; three homozygotes for Chuvash VHL 598C->T mutation; and a heterozygote for VHL 523->G mutation w...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2005-01-01 00:00:00
abstract::We report results of a phase II trial of combination of melphalan, lenalidomide, and dexamethasone for the treatment of immunoglobulin light chain (AL) amyloidosis. The primary objectives were tolerability and hematologic response rate; secondary objectives were organ responses and survival. Treatment protocol consist...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2012.075192
更新日期:2013-05-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:After allogeneic haematopoietic stem cell transplantation (SCT) the whole T-cell receptor (TCR) repertoire shows a markedly skewed pattern for 2-3 years. A small fraction of CD4+ T cells is represented by CD25+ regulatory lymphocytes (Treg), which play a crucial role in modulating peripheral t...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.10774
更新日期:2007-02-01 00:00:00
abstract:BACKGROUND:Acute myeloid leukemia is a clonal hematopoietic malignant disease; about 45-50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples. DESIGN AND...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.13024
更新日期:2009-02-01 00:00:00
abstract:BACKGROUND:The clonal origin of myeloproliferative disorders has been clearly demonstrated and it is known that reactive thrombocytosis occurs as a non specific response to various inflammatory or neoplastic conditions. Only a few papers have discussed the topic of myeloproliferative diseases in blood donors. MATERIAL...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1994-03-01 00:00:00
abstract::Chronic lymphocytic leukemia is a disease with up-regulated expression of the transmembrane tyrosine-protein kinase ROR1, a member of the Wnt/planar cell polarity pathway. In this study, we identified COBLL1 as a novel interaction partner of ROR1. COBLL1 shows clear bimodal expression with high levels in chronic lymph...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2017.178699
更新日期:2018-02-01 00:00:00
abstract::The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates phosphatidylinositol 3-kinase (PI3K)-AKT signaling and is often inactivated by mutations (including deletions) in a variety of cancer types, including T-cell acute lymphoblastic leukemia. Here we review mutation-associated mechanisms that ...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:10.3324/haematol.2016.146381
更新日期:2016-09-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:The aim of this study was to evaluate the tolerability and effectiveness of a non-myeloablative conditioning regimen followed by autologous hematopoietic stem cell infusion for the treatment of severe autoimmune diseases. DESIGN AND METHODS:From 1996 patients with severe autoimmune disease no...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2000-11-01 00:00:00
abstract::Hematologic responses to hypomethylating agents are often delayed in patients with myelodysplastic syndrome or acute myeloid leukemia. Fetal hemoglobin is a potential novel bio-marker of response: recently, we demonstrated that a high fetal hemoglobin level prior to decitabine treatment was associated with superior ou...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:10.3324/haematol.2017.187278
更新日期:2019-01-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human metabolic disorder in southern China. We investigated the incidence and distribution of mutations, the molecular pathology of affected females and the haplotype association with G6PD deficiency in patients from the Gu...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2006-10-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:High-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) has proven to be superior to conventional chemotherapy in patients with chemosensitive relapse of aggressive non-Hodgkin's lymphoma (NHL). Therefore, HDT/ASCT was evaluated as part of first-line therapy. Several...
journal_title:Haematologica
pub_type: 杂志文章,meta分析
doi:
更新日期:2003-11-01 00:00:00
abstract::A significant proportion of hematopoietic stem cell transplants are performed with ABO-mismatched donors. The impact of ABO mismatch on outcome following transplantation remains controversial and there are no published data regarding the impact of ABO mismatch in acute myeloid leukemia patients receiving haploidentica...
journal_title:Haematologica
pub_type: 杂志文章,多中心研究
doi:10.3324/haematol.2016.160804
更新日期:2017-06-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Serum beta(2)-microglobulin (s beta(2)m) is an established prognostic factor for multiple myeloma and non-Hodgkin's lymphoma, but only limited data suggest an adverse prognostic significance for Hodgkin's lymphoma (HL). This study was undertaken to examine the impact of s beta(2)m on the progn...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2002-07-01 00:00:00
abstract::High levels of HbF were found in patients with myelodysplastic syndrome (MDS), as well as a possible switching of the ratio of the gamma chains from the adult to the newborn type in 25% of our patients. These abnormalities in general were not present in the parents. The possibility of having thalassemia or other hemog...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1991-07-01 00:00:00
abstract::The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in 25-30% of patients with acute myeloid leukemia (AML). Because of the poor prognosis associated with FLT3-internal tandem duplication mutated AML, allogeneic hematopoietic stem-cell transplantation (SCT) was commonly performed in first complete remission. Remarka...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2019.243410
更新日期:2020-06-01 00:00:00
abstract::In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase togethe...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2016.144535
更新日期:2016-12-01 00:00:00
abstract:BACKGROUND:Thrombosis is the major risk factor for death in patients with paroxysmal nocturnal hemoglobinuria. Previous case reports indicate that venous thrombosis in patients with paroxysmal nocturnal hemoglobinuria is amenable to thrombolysis. DESIGN AND METHODS:We reviewed the outcome of thrombolytic therapy for p...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:10.3324/haematol.2011.049767
更新日期:2012-03-01 00:00:00
abstract::Hepcidin levels are high and iron absorption is limited in acute malaria. The mechanism(s) that regulate hepcidin secretion remain undefined. We have measured hepcidin concentration and cytokines in 100 Kenyan children with acute falciparum malaria and different degrees of anemia. Hepcidin was increased on admission a...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:10.3324/haematol.2012.065854
更新日期:2012-11-01 00:00:00
abstract::Our objective was to determine whether the goal of high-dose therapy should be a partial hematologic response or a complete response. We analyzed 282 consecutive stem cell transplant patients. A partial hematologic response was achieved in 108 patients (38%), and 93 (33%) achieved a complete hematologic response. Surv...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.11413
更新日期:2007-10-01 00:00:00
abstract::In order to overcome the problem of different control genes for BCR-ABL normalization, we used a linear regression equation to compare our results previously obtained using B2M as the control gene with those calculated using the ABL gene and validated the slope as a factor to convert from B2M to ABL results. ...
journal_title:Haematologica
pub_type: 信件
doi:10.3324/haematol.10632
更新日期:2007-03-01 00:00:00
abstract::The aim of this study was to identify new pathogenic variations of the UGT1A1 gene in 11 patients diagnosed with neonatal unconjugated hyperbilirubinemia. We describe two cases in which clinically unapparent heterozygotic mutations in the UGT1A1 gene may become evident in combination with certain environmental conditi...
journal_title:Haematologica
pub_type: 信件
doi:10.3324/haematol.10585
更新日期:2007-01-01 00:00:00