FLT3 activation cooperates with MLL-AF4 fusion protein to abrogate the hematopoietic specification of human ESCs.

Abstract:

:Mixed-lineage leukemia (MLL)-AF4 fusion arises prenatally in high-risk infant acute pro-B-lymphoblastic leukemia (pro-B-ALL). In human embryonic stem cells (hESCs), MLL-AF4 skewed hematoendothelial specification but was insufficient for transformation, suggesting that additional oncogenic insults seem required for MLL-AF4-mediated transformation. MLL-AF4+ pro-B-ALL expresses enormous levels of FLT3, occasionally because of activating mutations, thus representing a candidate cooperating event in MLL-AF4+ pro-B-ALL. Here, we explored the developmental impact of FLT3 activation alone, or together with MLL-AF4, in the hematopoietic fate of hESCs. FLT3 activation does not affect specification of hemogenic precursors but significantly enhances the formation of CD45(+) blood cells, and CD45(+)CD34(+) blood progenitors with clonogenic potential. However, overexpression of FLT3 mutations or wild-type FLT3 (FLT3-WT) completely abrogates hematopoietic differentiation from MLL-AF4-expressing hESCs, indicating that FLT3 activation cooperates with MLL-AF4 to inhibit human embryonic hematopoiesis. Cell cycle/apoptosis analyses suggest that FLT3 activation directly affects hESC specification rather than proliferation or survival of hESC-emerging hematopoietic derivatives. Transcriptional profiling of hESC-derived CD45(+) cells supports the FLT3-mediated inhibition of hematopoiesis in MLL-AF4-expressing hESCs, which is associated with large transcriptional changes and downregulation of genes involved in hematopoietic system development and function. Importantly, FLT3 activation does not cooperate with MLL-AF4 to immortalize/transform hESC-derived hematopoietic cells, suggesting the need of alternative (epi)-genetic cooperating hits.

journal_name

Blood

journal_title

Blood

authors

Bueno C,Ayllón V,Montes R,Navarro-Montero O,Ramos-Mejia V,Real PJ,Romero-Moya D,Araúzo-Bravo MJ,Menendez P

doi

10.1182/blood-2012-11-470146

subject

Has Abstract

pub_date

2013-05-09 00:00:00

pages

3867-78, S1-3

issue

19

eissn

0006-4971

issn

1528-0020

pii

blood-2012-11-470146

journal_volume

121

pub_type

杂志文章

相关文献

BLOOD文献大全
  • Characterization of influenza A virus activation of the human neutrophil.

    abstract::Neutrophil dysfunction consequent to influenza A virus infection has been described in vivo and in vitro and may contribute to the serious bacterial sequelae which occur in influenza-infected hosts. On the premise that such dysfunction may represent a form of "deactivation," we sought to characterize neutrophil activa...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Hartshorn KL,Collamer M,White MR,Schwartz JH,Tauber AI

    更新日期:1990-01-01 00:00:00

  • Pathologic effects of plasma from patients with thrombotic thrombocytopenic purpura on platelets and cultured vascular endothelial cells.

    abstract::The pathologic hallmarks of thrombotic thrombocytopenic purpura (TTP) include endothelial cell proliferation and subendothelial hyalin deposits in the microvasculature leading to symptomatic thrombotic occlusions. Plasma or sera from three consecutive patients with TTP were subjected to multiple analyses to determine ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Burns ER,Zucker-Franklin D

    更新日期:1982-10-01 00:00:00

  • Presence of functional dendritic cells in patients chronically infected with hepatitis C virus.

    abstract::The absence of expanded numbers of hepatitis C virus (HCV)-reactive CD8(+) T lymphocytes (CTLs) in patients chronically infected with HCV has led to the investigation of dendritic cell (DC) function in this population as a potential cause for this defect. Several studies have shown evidence for impaired monocyte-deriv...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-04-1339

    authors: Longman RS,Talal AH,Jacobson IM,Albert ML,Rice CM

    更新日期:2004-02-01 00:00:00

  • IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo.

    abstract::Interleukin 21 (IL-21) is a member of the common gamma-chain family of cytokines, which influence a broad spectrum of immunologic responses. A number of studies have examined the function of IL-21, but its specific role in Th1/Th2-cell differentiation and related effector responses remains to be clarified. Thus, we ge...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2006-05-021600

    authors: Fröhlich A,Marsland BJ,Sonderegger I,Kurrer M,Hodge MR,Harris NL,Kopf M

    更新日期:2007-03-01 00:00:00

  • Inhibition of human bone marrow fibroblast colony formation by leukemic cells.

    abstract::The number of bone marrow fibroblast colony formations decreases in most cases of acute leukemia before the initiation of chemotherapy. This study was undertaken to clarify the mechanism of suppression of fibroblast colony formation in leukemic patients. Titration of the number of bone marrow cells did not indicate a ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Nagao T,Yamauchi K,Komatsuda M,Noguchi K,Shimizu M,Yonekura S,Nozaki H

    更新日期:1983-12-01 00:00:00

  • Alloantigenic composition of the endothelial vitronectin receptor.

    abstract::Endothelial cells synthesize a heterodimeric adhesion molecule, the vitronectin receptor (VnR), which is similar to the platelet glycoprotein (GP)IIb/IIIa complex. The subunits of the endothelial VnR (VnR alpha and GPIIIa) have been studied for their ability to express alloantigens associated with platelet GPIIb and I...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Giltay JC,Leeksma OC,von dem Borne AE,van Mourik JA

    更新日期:1988-07-01 00:00:00

  • Fibrinogen Birmingham: a heterozygous dysfibrinogenemia (A alpha 16 Arg----His) containing heterodimeric molecules.

    abstract::Fibrinogen was isolated from the plasma of a 25-year-old female with a history of mild bleeding and several recent moderate to severe hemorrhagic episodes. Coagulability with thrombin approached 100% and varied directly with the time of incubation with the enzyme. High-performance liquid chromatography analysis of thr...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Siebenlist KR,Prchal JT,Mosesson MW

    更新日期:1988-03-01 00:00:00

  • Eosinophilic cytoplasmic inclusions in fetal leukocytes: are Auer bodies a recapitulation of fetal morphology?

    abstract::Among the most striking morphological features of acute nonlymphoblastic leukemias (ANLL) is the occurrence of eosinophilic cytoplasmic inclusions known as Auer rods on Auer bodies. We examined immature myeloid cells from the peripheral blood of 9 human fetuses of 16-19 wk gestation for the presence of such structures...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Newburger PE,Novak TJ,McCaffrey RP

    更新日期:1983-03-01 00:00:00

  • Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low-abundance mutant clones with early origins, but indicates no definite prognostic value.

    abstract::Mutations in the TET2 gene are frequent in myeloid disease, although their biologic and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using "next-generation" sequencing for TET2 aberrations, 91 of whom were also subjected to single-nucleotide polymorphism 6.0 array ka...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-03-274704

    authors: Smith AE,Mohamedali AM,Kulasekararaj A,Lim Z,Gäken J,Lea NC,Przychodzen B,Mian SA,Nasser EE,Shooter C,Westwood NB,Strupp C,Gattermann N,Maciejewski JP,Germing U,Mufti GJ

    更新日期:2010-11-11 00:00:00

  • Bradykinin regulates the expression of kininogen binding sites on endothelial cells.

    abstract::The vasoactive compound bradykinin (BK) is liberated by proteolytic cleavage from high molecular weight kininogen (HK) and low molecular weight kininogen (LK). Expression of kininogens on cell surface receptors may affect the delivery of BK at sites of inflammation. Therefore, we investigated whether BK itself alters ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Zini JM,Schmaier AH,Cines DB

    更新日期:1993-06-01 00:00:00

  • The Src kinase Lyn is required for CCR5 signaling in response to MIP-1beta and R5 HIV-1 gp120 in human macrophages.

    abstract::CCR5 is a receptor for several beta chemokines and the entry coreceptor used by macrophage-tropic (R5) strains of HIV-1. In addition to supporting viral entry, CCR5 ligation by the HIV-1 envelope glycoprotein 120 (gp120) can activate intracellular signals in macrophages and trigger inflammatory mediator release. Using...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2005-12-012815

    authors: Tomkowicz B,Lee C,Ravyn V,Cheung R,Ptasznik A,Collman RG

    更新日期:2006-08-15 00:00:00

  • Sex related differences in platelet function: the effect of aspirin.

    abstract::There is evidence from clinical studies and animal experiments that aspirin has a greater antithrombotic activity in males compared to females. We investigated platelet function in vitro and in vivo in rabbits before and after the administration of a dose of aspirin (5 mg/kg) which inhibited collagen stimulated thromb...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Kelton JG,Carter CJ,Santos A,Hirsh J

    更新日期:1982-03-01 00:00:00

  • X-linked lymphoproliferative syndromes: brothers or distant cousins?

    abstract::X-linked lymphoproliferative disease (XLP1), described in the mid-1970s and molecularly defined in 1998, and XLP2, reported in 2006, are prematurely lethal genetic immunodeficiencies that share susceptibility to overwhelming inflammatory responses to certain infectious triggers. Signaling lymphocytic activation molecu...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2010-03-275909

    authors: Filipovich AH,Zhang K,Snow AL,Marsh RA

    更新日期:2010-11-04 00:00:00

  • The immunotherapy era of myeloma: monoclonal antibodies, vaccines, and adoptive T-cell therapies.

    abstract::The treatment of multiple myeloma has evolved significantly over the last decades from primarily alkylator-based chemotherapeutic agents with minimal efficacy to the introduction of more effective agents including immune modulators and proteasome inhibitors, which have changed the landscape of therapy for this disease...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2016-05-636357

    authors: Hoyos V,Borrello I

    更新日期:2016-09-29 00:00:00

  • VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites.

    abstract::The mechanisms by which tumors metastasize to sentinel and distant lymph nodes, and beyond, are poorly understood. We developed transgenic mice that overexpress vascular endothelial growth factor-C (VEGF-C) and green fluorescent protein specifically in the skin and studied the effects of chemically-induced skin carcin...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2006-05-021758

    authors: Hirakawa S,Brown LF,Kodama S,Paavonen K,Alitalo K,Detmar M

    更新日期:2007-02-01 00:00:00

  • Regulation of proplatelet formation and platelet release by integrin alpha IIb beta3.

    abstract::Mature megakaryocytes form structures called proplatelets that serve as conduits for platelet packaging and release at vascular sinusoids. Since the megakaryocyte expresses abundant levels of integrin alpha IIb beta3, we have examined a role for fibrinogen in proplatelet development and platelet release alongside that...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2005-11-011957

    authors: Larson MK,Watson SP

    更新日期:2006-09-01 00:00:00

  • Death-defying apoptotic caspases in thrombopoiesis.

    abstract::In this issue of Blood, White et al provide compelling evidence that the intrinsic apoptotic caspase cascade, while required for megakaryocyte and platelet death under pathophysiologic conditions, is dispensable for normal platelet formation and function. ...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2012-02-410423

    authors: Cantor AB

    更新日期:2012-05-03 00:00:00

  • Quantification of the preexisting CD4 T-cell repertoire specific for human erythropoietin reveals its immunogenicity potential.

    abstract::Antibody-mediated pure red cell aplasia is a rare but serious event resulting from the induction of neutralizing erythropoietin (Epo)-specific antibodies provoked by treatment with recombinant Epo. Because of the crucial role of CD4 T cells in humoral response, we have quantified the number of Epo-specific CD4 T cells...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-04-280875

    authors: Delluc S,Ravot G,Maillere B

    更新日期:2010-11-25 00:00:00

  • Correction of hypercoagulability and amelioration of pulmonary arterial hypertension by chronic blood transfusion in an asplenic hemoglobin E/beta-thalassemia patient.

    abstract::Chronic transfusion of packed red blood cells, in addition to other ongoing treatment with warfarin, acetyl salicylic acid, desferrioxamine, and other supportive measures, was given to a splenectomized hemoglobin E/beta-thalassemia woman with pulmonary arterial hypertension (PHT). Serial measurements of plasma thrombi...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-09-3094

    authors: Atichartakarn V,Chuncharunee S,Chandanamattha P,Likittanasombat K,Aryurachai K

    更新日期:2004-04-01 00:00:00

  • SOX11 regulates PAX5 expression and blocks terminal B-cell differentiation in aggressive mantle cell lymphoma.

    abstract::Mantle cell lymphoma (MCL) is one of the most aggressive lymphoid neoplasms whose pathogenesis is not fully understood. The neural transcription factor SOX11 is overexpressed in most MCL but is not detected in other mature B-cell lymphomas or normal lymphoid cells. The specific expression of SOX11 in MCL suggests that...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2012-06-438937

    authors: Vegliante MC,Palomero J,Pérez-Galán P,Roué G,Castellano G,Navarro A,Clot G,Moros A,Suárez-Cisneros H,Beà S,Hernández L,Enjuanes A,Jares P,Villamor N,Colomer D,Martín-Subero JI,Campo E,Amador V

    更新日期:2013-03-21 00:00:00

  • HIT-antibodies promote their own antigen.

    abstract::Antiplatelet factor 4 (PF4) antibodies have an important role in the most frequent drug-induced immune disorder, heparin-induced thrombocytopenia (HIT). In this issue of Blood, Sachais and coworkers propose a new feature that may explain why only some anti-PF4 antibodies are pathogenic.(1) In addition to epitope speci...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2012-06-430694

    authors: Greinacher A,Krauel K,Jensch I

    更新日期:2012-08-02 00:00:00

  • A novel costimulatory signaling in human T lymphocytes by a splice variant of CD28.

    abstract::We have characterized a splice variant (isoform) of the human CD28 T cell costimulatory receptor. The nucleotide sequence of this CD28 isoform was identical to that of CD28 in the signal peptide, the transmembrane domain, and the cytoplasmic tail, but it was missing a large segment of the extracellular ligand-binding ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.v99.6.2138

    authors: Hanawa H,Ma Y,Mikolajczak SA,Charles ML,Yoshida T,Yoshida R,Strathdee CA,Litchfield DW,Ochi A

    更新日期:2002-03-15 00:00:00

  • Formation and functioning of the factor IXa-VIII complex on the surface of endothelial cells.

    abstract::The formation and functioning of the factor X activating complex on the surface of cultured human venous endothelial cells (HVEC) were investigated. To the HVEC monolayer human factors IXa, VIII, X, CaCl2, and S-2222 were added, and a gradually increasing activation of factor X was observed. The maximum activity of 88...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Váradi K,Elödi S

    更新日期:1987-02-01 00:00:00

  • Circulating thrombopoietin as an in vivo growth factor for blast cells in acute myeloid leukemia.

    abstract::Thrombopoietin (TPO), the major growth factor for cells of the megakaryocytic lineage, is removed from circulation by binding to c-mpl receptors present on platelets and megakaryocytes. We studied patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) and used TPO-induced c-fos protein u...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2005-06-2552

    authors: Corazza F,Hermans C,D'Hondt S,Ferster A,Kentos A,Benoît Y,Sariban E

    更新日期:2006-03-15 00:00:00

  • Studies on the basis for the properties of fibrin produced from fibrinogen-containing gamma' chains.

    abstract::Human fibrinogen 1 is homodimeric with respect to its gamma chains (gammaA-gammaA'), whereas fibrinogen 2 molecules each contain one gammaA (gammaA1-411V) and one gamma' chain, which differ by containing a unique C-terminal sequence from gamma'408 to 427L that binds thrombin and factor XIII. We investigated the struct...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2005-01-0240

    authors: Siebenlist KR,Mosesson MW,Hernandez I,Bush LA,Di Cera E,Shainoff JR,Di Orio JP,Stojanovic L

    更新日期:2005-10-15 00:00:00

  • Hertwig's anemia: characterization of the stem cell defect.

    abstract::Mice homozygous for Hertwig's anemia, an/an, have a mild macrocytic anemia and are refractory to the potentially curative action of exogenously administered erythropoietin (EP). Both red and white blood cell numbers are decreased. One possible explanation is that a precursor stem cell population is in short supply. We...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Barker JE,Bernstein SE

    更新日期:1983-04-01 00:00:00

  • Silent infections with human immunodeficiency virus type 1 are highly unlikely in multitransfused seronegative hemophiliacs.

    abstract::We used the polymerase chain reaction (PCR) to determine the frequency of silent human immunodeficiency virus type 1 (HIV-1) infections in seronegative high-risk individuals with hemophilia who had been exposed to contaminated blood products more than 3 years previously. In a cross-sectional study of a cohort of 57 pr...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Gibbons J,Cory JM,Hewlett IK,Epstein JS,Eyster ME

    更新日期:1990-11-15 00:00:00

  • Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan anemia patients: potential insights into pathophysiology.

    abstract::Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan anemia (DBA), a rare congenital hypoplastic anemia. Recent studies have shown that RPS19 expression decreases during terminal erythroid differentiation. Currently no information is available on the subcellular localization of normal RPS19 and the ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2002-12-3878

    authors: Da Costa L,Tchernia G,Gascard P,Lo A,Meerpohl J,Niemeyer C,Chasis JA,Fixler J,Mohandas N

    更新日期:2003-06-15 00:00:00

  • Inhibition of tartrate-resistant acid phosphatase gene expression by hemin and protoporphyrin IX. Identification of a hemin-responsive inhibitor of transcription.

    abstract::Tartrate-resistant acid phosphatase (TRAP) is an iron-containing protein encoded by the same gene that codes for uteroferrin, a placental iron transport protein. In human peripheral mononuclear cells, TRAP expression is inhibited by both hemin (ferric protoporphyrin IX) and protoporphyrin IX. Nuclear run-on assays con...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Reddy SV,Alcantara O,Roodman GD,Boldt DH

    更新日期:1996-09-15 00:00:00

  • How I treat acute myeloid leukemia in the era of new drugs.

    abstract::The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.2019001239

    authors: DiNardo CD,Wei AH

    更新日期:2020-01-09 00:00:00