The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression.

Abstract:

:Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9-guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of γ-globin transcription, by binding to its enhancer and fostering enhancer-promoter contacts. Notably, HRI-deficient mice display normal Bcl11a levels, suggesting species-selective regulation, which we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. Our studies uncover a linear signaling pathway from HRI to ATF4 to BCL11A to γ-globin and illustrate potential limits of murine models of globin gene regulation.

journal_name

Blood

journal_title

Blood

authors

Huang P,Peslak SA,Lan X,Khandros E,Yano JA,Sharma M,Keller CA,Giardine B,Qin K,Abdulmalik O,Hardison RC,Shi J,Blobel GA

doi

10.1182/blood.2020005301

subject

Has Abstract

pub_date

2020-06-11 00:00:00

pages

2121-2132

issue

24

eissn

0006-4971

issn

1528-0020

pii

454411

journal_volume

135

pub_type

杂志文章

相关文献

BLOOD文献大全
  • Heme oxygenase-1 expression enhances vascular endothelial resistance to complement-mediated injury through induction of decay-accelerating factor: a role for increased bilirubin and ferritin.

    abstract::Catabolism of free heme by heme oxygenase-1 (HO-1) generates carbon monoxide, biliverdin, and free iron (Fe). These end-products are responsible for much of the biologic activity of HO-1, including anti-inflammatory, antiapo-ptotic, antiproliferative, and antioxidant effects. We have identified an additional cytoprote...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2008-04-152934

    authors: Kinderlerer AR,Pombo Gregoire I,Hamdulay SS,Ali F,Steinberg R,Silva G,Ali N,Wang B,Haskard DO,Soares MP,Mason JC

    更新日期:2009-02-12 00:00:00

  • Organ-derived dendritic cells have differential effects on alloreactive T cells.

    abstract::Dendritic cells (DCs) are considered critical for the induction of graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). In addition to their priming function, dendritic cells have been shown to induce organ-tropism through induction of specific homing molecules on T cells. Using adoptive transfer ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2007-06-096602

    authors: Kim TD,Terwey TH,Zakrzewski JL,Suh D,Kochman AA,Chen ME,King CG,Borsotti C,Grubin J,Smith OM,Heller G,Liu C,Murphy GF,Alpdogan O,van den Brink MR

    更新日期:2008-03-01 00:00:00

  • Enrichment of human hematopoietic stem cell activity in the CD34+Thy-1+Lin- subpopulation from mobilized peripheral blood.

    abstract::The number of CD34+ cells in the peripheral blood of cancer patients is known to be increased following the administration of high dose chemotherapy and hematopoietic growth factors. These so-called peripheral blood stem cell grafts are now frequently used for autologous transplantation of patients with malignancies. ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Murray L,Chen B,Galy A,Chen S,Tushinski R,Uchida N,Negrin R,Tricot G,Jagannath S,Vesole D

    更新日期:1995-01-15 00:00:00

  • Mechanism for fetal hemoglobin induction by histone deacetylase inhibitors involves gamma-globin activation by CREB1 and ATF-2.

    abstract::The histone deacetylase inhibitors (HDA-CIs) butyrate and trichostatin A activate gamma-globin expression via a p38 mitogen-activating protein kinase (MAPK)-dependent mechanism. We hypothesized that down-stream effectors of p38 MAPK, namely activating transcription factor-2 (ATF-2) and cyclic AMP response element (CRE...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2006-01-023713

    authors: Sangerman J,Lee MS,Yao X,Oteng E,Hsiao CH,Li W,Zein S,Ofori-Acquah SF,Pace BS

    更新日期:2006-11-15 00:00:00

  • Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anemia.

    abstract::The introduction of immunosuppressive therapy for treatment of aplastic anemia has led to a considerable improvement in the prognosis of this disease. However, long-term follow-up of these patients showed a high incidence of "late" hematologic complications such as myelodysplasia and paroxysmal nocturnal hemoglobinuri...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Schubert J,Vogt HG,Zielinska-Skowronek M,Freund M,Kaltwasser JP,Hoelzer D,Schmidt RE

    更新日期:1994-04-15 00:00:00

  • Myeloma cells upregulate interleukin-6 secretion in osteoblastic cells through cell-to-cell contact but downregulate osteocalcin.

    abstract::Previous studies have shown that bone marrow, especially the bone microenvironment, may play an important role in the pathogenesis of multiple myeloma (MM). To elucidate the relationship between myeloma cells and bone cells, mainly osteoblasts, we have established a coculture system between two interleukin-6 (IL-6)-de...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Barillé S,Collette M,Bataille R,Amiot M

    更新日期:1995-10-15 00:00:00

  • Lineage-restricted expression of protein kinase C isoforms in hematopoiesis.

    abstract::The pattern of expression of several protein kinase C (PKC) isoforms (alpha, betaI, delta, epsilon, eta, and zeta) during the course of hematopoietic development was investigated using primary human CD34(+) hematopoietic cells and stable cell lines subcloned from the growth factor-dependent 32D murine hematopoietic ce...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Bassini A,Zauli G,Migliaccio G,Migliaccio AR,Pascuccio M,Pierpaoli S,Guidotti L,Capitani S,Vitale M

    更新日期:1999-02-15 00:00:00

  • Alloantigen presentation and graft-versus-host disease: fuel for the fire.

    abstract::Allogeneic stem cell transplantation (SCT) is a unique procedure, primarily in patients with hematopoietic malignancies, involving chemoradiotherapy followed by the introduction of donor hematopoietic and immune cells into an inflamed and lymphopenic environment. Interruption of the process by which recipient alloanti...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2016-02-697250

    authors: Koyama M,Hill GR

    更新日期:2016-06-16 00:00:00

  • The effect of alpha-thalassemia on the expression of the beta-thalassemia/HPFH heterozygote in a black family.

    abstract::A 2-yr-old black girl presented with a thalassemic clinical picture and was found to have nearly 100% fetal hemoglobin in her red cells. Pedigree analysis indicated that she was a heterozygote for the hereditary persistence of fetal hemoglobin gene and for a beta O-thalassemia gene. A brother, who also had nearly 100%...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Beutler E,Turner E,Kuhl W

    更新日期:1981-06-01 00:00:00

  • Generalized hexokinase deficiency in the blood cells of a patient with nonspherocytic hemolytic anemia.

    abstract::In a patient with nonspherocytic hemolytic anemia, a hexokinase deficiency was detected in the red cells (residual activity about 25% of normal) and in blood platelets (20%-35% of normal activity). Although the total hexokinase activity in lymphocytes was normal, the amount of hexokinase type I was decreased to about ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Rijksen G,Akkerman JW,van den Wall Bake AW,Hofstede DP,Staal GE

    更新日期:1983-01-01 00:00:00

  • Vaccination of human subjects expands both specific and bystander memory T cells but antibody production remains vaccine specific.

    abstract::Human subjects maintain long-term immunologic memory against infective organisms but the mechanism is unclear. CD4+ T-helper memory (Thmem) cells are pivotal in controlling humoral and cellular responses, therefore their longevity and response to vaccination are critical for maintenance of protective immunity. To prob...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2005-08-3255

    authors: Di Genova G,Roddick J,McNicholl F,Stevenson FK

    更新日期:2006-04-01 00:00:00

  • MHC class II cell-autonomously regulates self-renewal and differentiation of normal and malignant B cells.

    abstract::Best known for presenting antigenic peptides to CD4+ T cells, major histocompatibility complex class II (MHC II) also transmits or may modify intracellular signals. Here, we show that MHC II cell-autonomously regulates the balance between self-renewal and differentiation in B-cell precursors, as well as in malignant B...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2018-11-885467

    authors: Merkenschlager J,Eksmond U,Danelli L,Attig J,Young GR,Nowosad C,Tolar P,Kassiotis G

    更新日期:2019-03-07 00:00:00

  • Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial.

    abstract::Pretreatment cytogenetics is a known predictor of outcome in hematologic malignancies. However, its usefulness in adult acute lymphoblastic leukemia (ALL) is generally limited to the presence of the Philadelphia (Ph) chromosome because of the low incidence of other recurrent abnormalities. We present centrally reviewe...

    journal_title:Blood

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1182/blood-2006-10-051912

    authors: Moorman AV,Harrison CJ,Buck GA,Richards SM,Secker-Walker LM,Martineau M,Vance GH,Cherry AM,Higgins RR,Fielding AK,Foroni L,Paietta E,Tallman MS,Litzow MR,Wiernik PH,Rowe JM,Goldstone AH,Dewald GW,Adult Leukaemia Worki

    更新日期:2007-04-15 00:00:00

  • Unmaintained remissions in multiple myeloma.

    abstract::Twenty-eight patients with multiple myeloma responding to prior melphalan-prednisone combinations, but without additional chemotherapy, were followed until relapse. Patients receiving no further treatment had a median survival time similar to that of those receiving indefinite courses of melphalan-prednisone or carmus...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Alexanian R,Gehan E,Haut A,Saiki J,Weick J

    更新日期:1978-06-01 00:00:00

  • Extracellular histones induce erythrocyte fragility and anemia.

    abstract::Extracellular histones have been shown to play an important pathogenic role in many diseases, primarily through their cytotoxicity toward nucleated cells and their ability to promote platelet activation with resultant thrombosis and thrombocytopenia. In contrast, little is known about the effect of extracellular histo...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2017-06-790519

    authors: Kordbacheh F,O'Meara CH,Coupland LA,Lelliott PM,Parish CR

    更新日期:2017-12-28 00:00:00

  • Hydroxyurea makes inflammation "just right"?

    abstract::Hydroxyurea treatment of sickle cell mice improved their survival from pneumococcal pneumonia, counteracting the abnormally elevated inflammatory response and reducing invasion of bacteria into the bloodstream, through down regulation of E-selectin. ...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2011-12-397794

    authors: Hsu LL

    更新日期:2012-02-23 00:00:00

  • Neuromedin U: a Myb-regulated autocrine growth factor for human myeloid leukemias.

    abstract::The c-myb proto-oncogene has been implicated in leukemogenesis, but possible mechanisms remain ill defined. To gain further insight to this process, we used transcript profiling in K562 cells expressing a dominant-negative Myb (MERT) protein. A total of 105 potential Myb gene targets were identified. Neuromedin U (NmU...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2003-10-3577

    authors: Shetzline SE,Rallapalli R,Dowd KJ,Zou S,Nakata Y,Swider CR,Kalota A,Choi JK,Gewirtz AM

    更新日期:2004-09-15 00:00:00

  • Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine.

    abstract::The generation of Ab-secreting plasma cells depends critically on CD4 T-follicular helper (TFH) cells during the germinal center reaction. Germinal center TFH cells share functional properties with circulating CXCR5(+) CD4 T cells, referred to herein as peripheral TFH (pTFH) cells. Because deficient Ab production and ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2011-12-396648

    authors: Pallikkuth S,Parmigiani A,Silva SY,George VK,Fischl M,Pahwa R,Pahwa S

    更新日期:2012-08-02 00:00:00

  • Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs.

    abstract::A role for microRNA (miRNA) has been recognized in nearly every biologic system examined thus far. A complete delineation of their role must be preceded by the identification of all miRNAs present in any system. We elucidated the complete small RNA transcriptome of normal and malignant B cells through deep sequencing ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2010-05-285403

    authors: Jima DD,Zhang J,Jacobs C,Richards KL,Dunphy CH,Choi WW,Au WY,Srivastava G,Czader MB,Rizzieri DA,Lagoo AS,Lugar PL,Mann KP,Flowers CR,Bernal-Mizrachi L,Naresh KN,Evens AM,Gordon LI,Luftig M,Friedman DR,Weinberg JB

    更新日期:2010-12-02 00:00:00

  • Spurious E rosette formation in B cell chronic lymphocytic leukemia due to monoclonal anti-sheep RBC antibody.

    abstract::The apparent simultaneous presence of surface markers characteristic of both B and T cells is a phenomenon being described with increasing frequency in patients with chronic lymphocytic leukemia (CLL). We describe a patient with CLL whose B lymphocytes possessed surface immunoglobulin reactive with neuraminidase-treat...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Mills LE,O'Donnell JF,Guyre PM,LeMarbre PJ,Miller JD,Bernier GM

    更新日期:1985-02-01 00:00:00

  • ADAMTS13 turns 3.

    abstract::It has now been 3 years since the von Willebrand factor (VWF)-cleaving protease implicated in thrombocytopenic purpura (TTP) pathogenesis was identified as ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13). More than 50 ADAMTS13 mutations resulting in familial TTP have been reported...

    journal_title:Blood

    pub_type: 杂志文章,评审

    doi:10.1182/blood-2004-10-4097

    authors: Levy GG,Motto DG,Ginsburg D

    更新日期:2005-07-01 00:00:00

  • Restoration of sensitivity to STI571 in STI571-resistant chronic myeloid leukemia cells.

    abstract::STI571 induces sustained hematologic remission in patients with chronic myeloid leukemia (CML) in chronic phase. However, in advanced phases, especially blast crisis, the leukemia usually becomes resistant within months. It has been investigated whether resistance to STI571 is stable and immutable or whether it can be...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.v98.13.3864

    authors: Tipping AJ,Mahon FX,Lagarde V,Goldman JM,Melo JV

    更新日期:2001-12-15 00:00:00

  • Tissue factor pathway inhibitor is required for cerebrovascular development in mice.

    abstract::Tissue factor pathway inhibitor (TFPI) inhibits proteases in the blood coagulation cascade that lead to the production of thrombin, including prothrombinase (factor Xa [FXa]/FVa), the catalytic complex that directly generates thrombin. Thus, TFPI and FV are directly linked in regulating the procoagulant response. Stud...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood.2020006054

    authors: Maroney SA,Westrick RJ,Cleuren AC,Martinez ND,Siebert AE,Zogg M,Ginsburg D,Weiler H,Mast AE

    更新日期:2021-01-14 00:00:00

  • Identification of a restriction fragment length polymorphism involving the oncogene ETS-1 on chromosome 11q23.

    abstract::Twenty four samples of DNA from 23 unrelated individuals were analyzed for the presence of a novel restriction fragment length polymorphism (RFLP) involving the proto-oncogene ETS-1 at an Xba I site. Four samples from unrelated individuals lacked an Xba I site, giving rise to a longer restriction fragment detectable b...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Savage PD,Hanson CA,Kersey JH

    更新日期:1987-07-01 00:00:00

  • Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans.

    abstract::Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity....

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Granowitz EV,Porat R,Mier JW,Orencole SF,Callahan MV,Cannon JG,Lynch EA,Ye K,Poutsiaka DD,Vannier E

    更新日期:1993-11-15 00:00:00

  • Hydrodynamic shear shows distinct roles for LFA-1 and Mac-1 in neutrophil adhesion to intercellular adhesion molecule-1.

    abstract::The binding of neutrophil beta2 integrin to intercellular adhesion molecule-1 (ICAM-1) expressed on the inflamed endothelium is critical for neutrophil arrest at sites of tissue inflammation. To quantify the strength and kinetics of this interaction, we measured the adhesion between chemotactically stimulated neutroph...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Neelamegham S,Taylor AD,Burns AR,Smith CW,Simon SI

    更新日期:1998-09-01 00:00:00

  • Alternating v repeated postremission treatment in adult acute myelogenous leukemia: a randomized phase III study (AML6) of the EORTC Leukemia Cooperative Group.

    abstract::The value of a postremission treatment in acute myelogenous leukemia (AML), with alternating combinations of non-cross-resistant drugs, has been prospectively assessed. Of 515 evaluable patients, 347 (67.4%) entered into complete remission (CR), following induction treatment with daunorubicin (DNR), vincristine (VCR),...

    journal_title:Blood

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:

    authors: Zittoun R,Jehn U,Fière D,Haanen C,Löwenberg B,Willemze R,Abels J,Bury J,Peetermans M,Hayat M

    更新日期:1989-03-01 00:00:00

  • Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway.

    abstract::Type 1 T regulatory (Tr1) cells suppress immune responses in vivo and in vitro and play a key role in maintaining tolerance to self- and non-self-antigens. Interleukin-10 (IL-10) is the crucial driving factor for Tr1 cell differentiation, but the molecular mechanisms underlying this induction remain unknown. We identi...

    journal_title:Blood

    pub_type: 杂志文章

    doi:10.1182/blood-2009-07-234872

    authors: Gregori S,Tomasoni D,Pacciani V,Scirpoli M,Battaglia M,Magnani CF,Hauben E,Roncarolo MG

    更新日期:2010-08-12 00:00:00

  • Why "R" HIT patients predisposed to thrombosis?

    abstract::In this issue of Blood, Rollin et al demonstrate that heparin-induced thrombocytopenia and thrombosis (HIT) patients homozygous for arginine (R) at position 131 in the immunoglobulin (Ig)G receptor FcγRIIA have a significantly higher incidence of thrombosis, and show that plasma IgG may play a key role in modulating t...

    journal_title:Blood

    pub_type: 评论,杂志文章

    doi:10.1182/blood-2015-02-629782

    authors: Padmanabhan A

    更新日期:2015-04-09 00:00:00

  • Downregulation of interleukin-12 (IL-12) responsiveness in human T cells by transforming growth factor-beta: relationship with IL-12 signaling.

    abstract::Interleukin-12 (IL-12) is a cytokine that plays a central role in the control of cell-mediated immunity. We have previously shown that transforming growth factor-beta1 (TGF-beta) inhibitory effects on human primary allogeneic cytotoxicity and proliferative responses interfere with IL-12 pathway. The present study was ...

    journal_title:Blood

    pub_type: 杂志文章

    doi:

    authors: Pardoux C,Ma X,Gobert S,Pellegrini S,Mayeux P,Gay F,Trinchieri G,Chouaib S

    更新日期:1999-03-01 00:00:00