Abstract:
:The immunomodulatory drugs, lenalidomide and pomalidomide yield high response rates in multiple myeloma patients, but are associated with a high rate of thrombocytopenia and increased risk of secondary hematologic malignancies. Here, we demonstrate that the immunomodulatory drugs induce self-renewal of hematopoietic progenitors and upregulate megakaryocytic colonies by inhibiting apoptosis and increasing proliferation of early megakaryocytic progenitors via down-regulation of IKZF1. In this process, the immunomodulatory drugs degrade IKZF1 and subsequently down-regulate its binding partner, GATA1. This results in the decrease of GATA1 targets such as ZFPM1 and NFE2, leading to expansion of megakaryocytic progenitors with concomitant inhibition of maturation of megakaryocytes. The down-regulation of GATA1 further decreases CCND1 and increases CDKN2A expression. Overexpression of GATA1 abrogated the effects of the immunomodulatory drugs and restored maturation of megakaryocytic progenitors. Our data not only provide the mechanism for the immunomodulatory drugs induced thrombocytopenia but also help to explain the higher risk of secondary malignancies and long-term cytopenia induced by enhanced cell cycling and subsequent exhaustion of the stem cell pool.
journal_name
Haematologicajournal_title
Haematologicaauthors
Liu A,Li S,Donnenberg V,Fu J,Gollin SM,Ma H,Lu C,Stolz DB,Mapara MY,Monaghan SA,Lentzsch Sdoi
10.3324/haematol.2018.188227subject
Has Abstractpub_date
2018-10-01 00:00:00pages
1688-1697issue
10eissn
0390-6078issn
1592-8721pii
haematol.2018.188227journal_volume
103pub_type
杂志文章相关文献
HAEMATOLOGICA文献大全abstract:BACKGROUND AND OBJECTIVE:To compare the clinical results of two consecutive therapeutic protocols including autologous blood stem cell transplantation (ABSCT) for patients with de novo acute myeloblastic leukemia (AML) in first complete remission (CR1). DESIGN AND METHODS:Between November 1989 and January 1997, 50 pat...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:
更新日期:1999-02-01 00:00:00
abstract::Even though alterations in platelet counts are presumed to be detrimental, their impact on the survival of patients has not been studied in large cohorts. The prevalence of thrombocytopenia and thrombocytosis was examined in a large inner city outpatient population of 36,262 individuals aged ≥65 years old. A significa...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2013.101949
更新日期:2014-05-01 00:00:00
abstract::The role of reduced intensity allogeneic stem cell transplantation for the treatment of relapsed/refractory Hodgkin's lymphoma remains controversial. We retrospectively analyzed 191 patients who underwent reduced intensity allogeneic stem cell transplantation between 1998 and 2008 for relapsed or refractory Hodgkin's ...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2012.080895
更新日期:2013-09-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:The efficacy and safety of added dexamethasone were assessed in patients with relapsed and/or refractory multiple myeloma who had a suboptimal response to bortezomib alone. DESIGN AND METHODS:In two previously reported, open-label, multicenter phase 2 studies, bortezomib 1.0 or 1.3 mg/m2 was ...
journal_title:Haematologica
pub_type: 杂志文章,多中心研究,随机对照试验
doi:
更新日期:2006-07-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Human immunodeficiency virus (HIV) infection was transmitted to many hemophilics treated with non-inactivated factor concentrates before 1986. The aim of this study was to know the long-term incidence of AIDS and risk factors for its development in HIV-infected hemophiliacs. DESIGN AND METHOD...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2001-03-01 00:00:00
abstract::Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis vir...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.12554
更新日期:2008-08-01 00:00:00
abstract:BACKGROUND:MicroRNAs can play an important role in tumorigenesis through post-transcriptional regulation of gene expression, and are not well characterized in follicular lymphoma. DESIGN AND METHODS:MicroRNA profiles of enriched follicular lymphoma tumor cells from 16 patients were generated by assaying 851 human micr...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2011.048132
更新日期:2012-04-01 00:00:00
abstract::As in other malignancies, peripheral blood progenitor cells (PBPC) have almost completely replaced bone marrow as the source of stem cells for autologous transplantation in multiple myeloma. PBPC collection could be optimized either by reducing contamination by the malignant clone or by increasing hematopoietic qualit...
journal_title:Haematologica
pub_type: 临床试验,杂志文章,随机对照试验,评审
doi:
更新日期:1999-06-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:Abnormalities in the expression of cell adhesion molecules (CAM) are thought to influence the patterns of intranodal growth and hematogeneous spread of malignant cells in chronic lymphoproliferative disorders (LPD). Therefore, the characterization of CAM phenotypic profiles of the neoplastic cl...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1998-02-01 00:00:00
abstract::Over the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important research tool in the field. The most significant contributions made by means of humanized mice are the identification of...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:10.3324/haematol.2014.115212
更新日期:2016-01-01 00:00:00
abstract::BCL11A was the focus of recent studies on its inhibiting effect when bound onto the β-globin cluster in the mechanism of hemoglobin switching and HbF downregulation. We examined a cohort of 10 patients displaying different HbF levels and short deletions within the γβ-δ intergenic region to find a possible correlation ...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2012.061994
更新日期:2013-02-01 00:00:00
abstract:BACKGROUND:Epigenetic changes are involved in the extinction of the B-cell gene expression program of classical Hodgkin's lymphoma. However, little is known regarding epigenetic similarities between cells of classical Hodgkin's lymphoma and plasma cell myeloma, both of which share extinction of the gene expression prog...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2010.031138
更新日期:2011-06-01 00:00:00
abstract::Circulating plasma thrombomodulin (TM) is an endothelial cell marker which may reflect endothelial injury. To find out to what extent diagnostic cardiac catheterization irritates vascular endothelium we conducted a prospective study in 91 children. Soluble TM concentrations, along with thrombin generation, were measur...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::As the defective genes for more and more genetic disorders become unravelled, it is clear that patients with apparently identical genotypes can have many different clinical conditions even in simple monogenic disorders. Beta thalassemia occurs when there is a deficiency in the synthesis of beta globin chains. The clin...
journal_title:Haematologica
pub_type: 杂志文章,评审
doi:
更新日期:2005-05-01 00:00:00
abstract:BACKGROUND:The World Health Organization separates acute erythroid leukemia (erythropoiesis in ≥50% of nucleated bone marrow cells; ≥20% myeloblasts of non-erythroid cells) from other entities with increased erythropoiesis - acute myeloid leukemia with myelodysplasia-related changes (≥20% myeloblasts of all nucleated c...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2011.043687
更新日期:2011-09-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:Levels of intracellular bcl-2 oncoprotein have been found to be increased in leukemic cells of CD5+ B-chronic lymphocytic leukemia (CLL) patients. However, it is not clear whether bcl-2 overexpression is a peculiar feature of CD5+ B-CLL. Based on this background we carried out a quantitative f...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1997-09-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:A D-dimer assay can be helpful to rule out thromboembolism provided it is sensitive, reliable, fast and easy to perform. Tests based on the ELISA methodology have a high diagnostic sensitivity, and are therefore adequate for excluding deep venous thrombosis (DVT). The drawbacks are their long a...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2000-05-01 00:00:00
abstract:BACKGROUND:The suppression of Ph1-positive hemopoiesis is a major goal in the treatment of CML; in this context the CML patients in blast crisis obtaining a complete clinical remission represent a useful model to investigate the behavior of the Ph1-positive and negative clones during bone marrow repopulation after abla...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1991-03-01 00:00:00
abstract:BACKGROUND:Mutation C1149R in the von Willebrand factor (VWF) gene has been thought to cause autosomal dominant severe type 1 von Willebrand disease (VWD). DESIGN AND METHODS:Eight patients from three unrelated families with this mutation were included in the present study who had distinct VWF abnormalities, not descr...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2008.003301
更新日期:2009-05-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:We previously found a high-level amplification in chromosomal region 21q22 in two children with acute lymphoblastic leukemia (ALL) using comparative genomic hybridization. The same region harbors the AML1 gene. The aim of the present study was to investigate whether AML1 is a target gene in the...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2000-04-01 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::B-cell chronic lymphocytic leukemia-related genomic changes were analyzed by karyotyping, fluorescence in situ hybridization, and V(H) gene sequencing in a prospective clinical evaluation. The V(H) mutational status correlated with high-risk cytogenetic aberrations while no such relation could be demonstrated for spec...
journal_title:Haematologica
pub_type: 信件
doi:
更新日期:2006-10-01 00:00:00
abstract:BACKGROUND AND OBJECTIVE:A prospective study to evaluate the role of fludarabine alone or in combination with idarubicin in untreated patients with mantle cell lymphoma (MCL). DESIGN AND METHODS:Twenty-nine untreated patients with mantle cell lymphoma were stochastically treated with intravenous fludarabine at a dose ...
journal_title:Haematologica
pub_type: 临床试验,杂志文章
doi:
更新日期:1999-11-01 00:00:00
abstract::We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m2 and allogeneic hematopoietic cell transplantation. Here we present l...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.2018.200253
更新日期:2019-02-01 00:00:00
abstract:BACKGROUND AND OBJECTIVES:We investigated outcomes in a UK neonatal cohort as a benchmark for care of children with sickle cell disease (SCD). DESIGN AND METHODS:Two-hundred and fifty-two children (180 with hemoglobin [Hb] SS, 64 with HbSC, and 8 with HbS/beta thalassemia), identified during 1983-2005 by universal bir...
journal_title:Haematologica
pub_type: 杂志文章
doi:10.3324/haematol.10937
更新日期:2007-07-01 00:00:00
abstract::This study aimed at evaluating the effectiveness of alpha interferon (IFN) in chronic myelomonocytic leukemia, a disease for which therapeutic options are still unsatisfactory. Fourteen sequential unselected patients received recombinant alpha-2b IFN (Intron-A, Schering-Essex) 3 megaU/day, progressively elevated to 10...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1989-11-01 00:00:00
abstract::Granulocyte activation parameters have been described in patients with myeloproliferative disorders (MPD). We have evaluated the accuracy of leukocyte alkaline phosphatase (LAP) score to predict JAK2 V617F mutation. LAP score was obtained using a cytochemical reaction in granulocytes of patients' peripheral blood with...
journal_title:Haematologica
pub_type: 信件
doi:10.3324/haematol.10991
更新日期:2007-05-01 00:00:00
abstract::Primary vaginal non-Hodgkin lymphoma is really uncommon and may be misdiagnosed as inflammatory disease or solid cancer, so careful diagnostic procedures are needed, particularly as far as pathological and immunocytochemical evaluation is concerned. Most of these lymphomas present with follicular patterns and limited ...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:1994-03-01 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:BACKGROUND AND OBJECTIVES:Loss of heterozygosity (LOH) on the long arm of chromosome 7 (7q) has been frequently reported in several types of human cancer including hematologic malignancies. Moreover, monosomy of chromosome 7 and 7q deletions have been associated in acute myeloid leukemia (AML) with aggressive disease a...
journal_title:Haematologica
pub_type: 杂志文章
doi:
更新日期:2003-04-01 00:00:00