Abstract:
:The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream of FLT3 signaling. The drug combination induced synergistic inhibition of proliferation, as well as enhanced apoptosis, compared with single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary acute myeloid leukemia (AML) cells harvested from patients with NPM1mutFLT3mut AML showed significantly better responses to combined menin and FLT3 inhibition than to single-drug or vehicle control treatment, whereas AML cells with wild-type NPM1, MLL, and FLT3 were not affected by either of the 2 drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared with results in the single-drug and vehicle control groups. Our data suggest that combined menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.
journal_name
Bloodjournal_title
Bloodauthors
Dzama MM,Steiner M,Rausch J,Sasca D,Schönfeld J,Kunz K,Taubert MC,McGeehan GM,Chen CW,Mupo A,Hähnel P,Theobald M,Kindler T,Koche RP,Vassiliou GS,Armstrong SA,Kühn MWMdoi
10.1182/blood.2020005037subject
Has Abstractpub_date
2020-11-19 00:00:00pages
2442-2456issue
21eissn
0006-4971issn
1528-0020pii
461196journal_volume
136pub_type
杂志文章相关文献
BLOOD文献大全abstract::Crystal formation by monoclonal immunoglobulins is a well-known but rare complication of B-cell neoplasia. We have designed an in vivo model of cryocrystalglobulinemia by grafting to mice hybridoma clones producing a pathogenic monoclonal immunogloblulin (Ig) G3kappa. One clone, 8A4, secreted a singular IgG3 that form...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:2000-06-01 00:00:00
abstract::Deletion of Runx1 in adult mice produces a myeloproliferative phenotype. We now find that Runx1 gene deletion increases marrow monocyte while reducing granulocyte progenitors and that exogenous RUNX1 rescues granulopoiesis. Deletion of Runx1 reduces Cebpa mRNA in lineage-negative marrow cells and in granulocyte-monocy...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-12-397091
更新日期:2012-05-10 00:00:00
abstract::The initiation and progression of diffuse large B-cell lymphoma (DLBCL) is governed by genetic and epigenetic aberrations. As the most abundant eukaryotic message RNA modification, N6-methyladenosine (m6A) is known to influence various fundamental bioprocesses by regulating target gene; however, the function of m6A mo...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.2019003764
更新日期:2020-09-23 00:00:00
abstract::Healthy blood neutrophils are functionally quiescent in the bloodstream, have a short lifespan, and exit the circulation to carry out innate immune functions, or undergo rapid apoptosis and macrophage-mediated clearance to mitigate host tissue damage. Limitation of unnecessary intravascular neutrophil activation is al...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-11-751636
更新日期:2017-06-08 00:00:00
abstract::Production of a red blood cell's hemoglobin depends on mitochondrial heme synthesis. However, mature red blood cells are devoid of mitochondria and rely on glycolysis for ATP production. The molecular basis for the selective elimination of mitochondria from mature red blood cells remains controversial. Recent evidence...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2008-02-137398
更新日期:2008-08-15 00:00:00
abstract::Protein Z is a vitamin K-dependent glycoprotein that plays a role in the regulation of coagulation. A nucleotide substitution of G by C in exon II of the protein Z gene, resulting in the replacement of Glu-30 with Gln (E30Q), and a G to A transition at the 79th nucleotide in intron F (IntF79G/A) were heterozygously id...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2004-06-2250
更新日期:2005-04-15 00:00:00
abstract::CTLA-4 is a critical inhibitory "checkpoint" molecule of immune activation. Several recent reports have described patients with immune dysregulation and lymphoproliferative disease resulting from 2 different genetic diseases that directly or indirectly cause CTLA-4 deficiency. Numerous articles have also been publishe...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2016-04-712612
更新日期:2016-08-25 00:00:00
abstract::Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consec...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-04-1311
更新日期:2004-01-01 00:00:00
abstract::A primary function of the World Marrow Donor Association is to establish general guidelines covering collaboration between international donor registries and practice in regard to bone marrow transplants (BMTs) in which the donor and recipient reside in different countries. To this end, a special report proposing spec...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1994-11-01 00:00:00
abstract::To study outcomes of adults with idiopathic thrombocytopenic purpura (ITP), we performed a follow-up study in a cohort of 152 consecutive patients who were treated according to a well-defined algorithm. Long-term outcomes were determined relative to the response 2 years after diagnosis, because most (93%) patients who...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.9.2549
更新日期:2001-05-01 00:00:00
abstract::Oxygen-induced retinopathy (OIR) is a well-characterized model for retinopathy of prematurity, a disorder that results from rapid microvascular proliferation after exposure of the retina to high oxygen levels. Here, we report that the proliferative phase of OIR requires transcriptional induction of the annexin A2 (A2)...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-03-341214
更新日期:2011-09-08 00:00:00
abstract::An understanding of mechanisms regulating hematopoietic stem cell engraftment is of pivotal importance to the clinical use of cultured and genetically modified transplants. Human cord blood (CB) cells with lymphomyeloid repopulating activity in NOD/SCID mice were recently shown to undergo multiple self-renewal divisio...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:2000-12-15 00:00:00
abstract::Loxosceles is the most venomous spider in Brazil, and envenomation causes dermonecrosis and complement (C)-dependent intravascular hemolysis. The authors studied the mechanism of induction of C-induced hemolysis. Purified Loxosceles toxins rendered human erythrocytes susceptible to lysis by human C but did not have an...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:2000-01-15 00:00:00
abstract::A simple and reliable cytogenetic test for Fanconi's anemia (FA) that is based on the hypersensitivity of FA cells to mitomycin C (MC) is described. Equal volumes of whole blood from a patient in whom the diagnosis of FA is suspected and from a normal person of the opposite sex are co-cultured in phytohemagglutinin-co...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1987-06-01 00:00:00
abstract::Mesenchymal stem cells (MSCs) are multipotent progenitor cells that have emerged as a promising tool for clinical application. Further clinical interest has been raised by the observation that MSCs are immunoprivileged and, more important, display immunosuppressive capacities. These properties may be of therapeutic va...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2005-11-011650
更新日期:2006-09-15 00:00:00
abstract::The functional activities of the tumor suppressor promyelocytic leukemia protein (PML) are mostly associated with its nuclear location. In the present study, we discovered an unexpected role of PML in NLRP3 inflammasome activation. In PML-deficient macrophages, the production of IL-1β was strongly impaired. The expres...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2012-05-432104
更新日期:2013-04-18 00:00:00
abstract::Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalatio...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.2020007197
更新日期:2020-12-24 00:00:00
abstract::Recovery of dendritic cells (DCs) and natural killer (NK) cells after allogeneic stem cell transplantation (SCT) is important for allograft responses and antitumor immunity and thus for treatment outcome. Regulation of this regenerative process is not well understood. We investigated the influence of endogenous cytoki...
journal_title:Blood
pub_type: 临床试验,杂志文章
doi:10.1182/blood-2003-04-1200
更新日期:2004-05-15 00:00:00
abstract::An antigen-capture sandwich enzyme-linked immunosorbent assay (ELISA) was developed for a novel protein granulophysin, a constituent of the platelet dense granule (DG) membrane and used to characterize patients with dense granule storage pool deficiency (delta-SPD). The assay uses two monoclonal antibodies against the...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1992-09-01 00:00:00
abstract::Reticulocytes release small membrane vesicles termed exosomes during their maturation into erythrocytes. It has been suggested that reticulocytes remodel the plasma membrane of the immature red cell during erythropoiesis by specifically eliminating various proteins. We report here that exosome release is associated wi...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-04-085845
更新日期:2007-11-01 00:00:00
abstract::Interferon (IFN) consensus sequence-binding protein (ICSBP) is an important transcription factor regulating proinflammatory cytokine production and the development of mononuclear phagocytes in vitro. Here we analyzed the role of ICSBP in the in vivo differentiation of 3 major subsets of murine dendritic cells (DCs). W...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-04-1088
更新日期:2003-01-01 00:00:00
abstract::Human invariant natural killer T (iNKT) cells are a rare innate-like lymphocyte population that recognizes glycolipids presented on CD1d. Studies in mice have shown that these cells are heterogeneous and are capable of enacting diverse functions, and the composition of iNKT cell subsets can alter disease outcomes. In ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.2019001903
更新日期:2020-03-12 00:00:00
abstract::Chronic infection with Schistosoma mansoni induces in humans and mice a Th2-dominant immune response in which eosinophils and IgE are conspicuously elevated. Human eosinophils express IgE receptors that participate in an IgE-dependent eosinophil-mediated ADCC reaction against Schistosomula larvae in vitro. To investig...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-05-15 00:00:00
abstract::All cases of multiple myeloma (MM) are preceded by precursor states termed monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). Genetic analyses of MGUS cells have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes found i...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2016-09-692954
更新日期:2016-12-08 00:00:00
abstract::The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; c...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.11.3628
更新日期:2001-06-01 00:00:00
abstract::Down-regulation of immune responses by regulatory T (Treg) cells is an important mechanism involved in the induction of tolerance to allo-antigens (Ags). Recently, a novel subset of Ag-specific T-cell receptor (TCR)alpha beta+ CD4(-)CD8- (double-negative [DN]) Treg cells has been found to be able to prevent the reject...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2004-07-2583
更新日期:2005-04-01 00:00:00
abstract::Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were ...
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2012-02-414631
更新日期:2012-08-09 00:00:00
abstract::Pruritus is a common symptom in patients with Philadelphia chromosome-negative myeloproliferative disorders (MPDs). The pathophysiology of MPD-associated pruritus is unclear. We have demonstrated that MPD mast cells (MCs) are involved by the malignant process. In the present study, we explored the hypothesis that MCs ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2008-09-179416
更新日期:2009-06-04 00:00:00
abstract::Sickle cell anemia (SCA) is an inherited disorder of beta-globin, resulting in red blood cell rigidity, anemia, painful crises, organ infarctions, and reduced life expectancy. Allogeneic blood or marrow transplantation (BMT) can cure SCA but is associated with an 8% to 10% mortality rate, primarily from complications ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.12.3960
更新日期:2001-06-15 00:00:00
abstract::Accumulating evidence has designated B cells as central players in the pathogenesis of immune diseases. In the late 1990s, anti-CD20 monoclonal antibodies were developed for the treatment of B-cell non-Hodgkin lymphomas, offering the opportunity to efficiently deplete the B-cell compartment for therapeutic immunointer...
journal_title:Blood
pub_type: 杂志文章,评审
doi:10.1182/blood-2010-01-266668
更新日期:2010-07-29 00:00:00