JAK inhibitors suppress t(8;21) fusion protein-induced leukemia.

Abstract:

:Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein acute myeloid leukemia (AML)1-ETO and its alternatively spliced variant AML1-ETO9a (AE9a) enhance the JAK/STAT pathway via downregulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML.

journal_name

Leukemia

journal_title

Leukemia

authors

Lo MC,Peterson LF,Yan M,Cong X,Hickman JH,Dekelver RC,Niewerth D,Zhang DE

doi

10.1038/leu.2013.197

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

2272-9

issue

12

eissn

0887-6924

issn

1476-5551

pii

leu2013197

journal_volume

27

pub_type

杂志文章

相关文献

LEUKEMIA文献大全
  • Expression of the LH2 gene in chronic myeloid leukaemia cells.

    abstract::The LH2 gene encodes a putative transcription factor containing two N-terminal LIM and one C-terminal HOX domains. The LH2 locus was mapped to 9q33-34.1, centromeric to the ABL gene. In a recent report, it was suggested that high levels of LH2 expression are consistently observed in chronic myeloid leukemia (CML) pati...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Al-Jehani F,Hochhaus A,Spencer A,Goldman JM,Melo JV

    更新日期:1996-07-01 00:00:00

  • Therapy of acute phase chronic myelogenous leukemia with intensive chemotherapy, blood cell autotransplant and cyclosporine A.

    abstract::The expansion of the Philadelphia (Ph) chromosome positive clone in chronic myeloid leukemia (CML) may depend on its capacity to suppress the proliferation of Ph-negative stem cells, but this proliferative advantage might, in certain circumstances, be reversible. Various lines of evidence suggest that Ph-negative cell...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Carella AM,Gaozza E,Raffo MR,Carlier P,Frassoni F,Valbonesi M,Lercari G,Sessarego M,Defferrari R,Guerrasio A

    更新日期:1991-06-01 00:00:00

  • Interleukin-6 autoantibodies: possible biological and clinical significance.

    abstract::The pleiotropic cytokines, interleukin (IL)-1 alpha, type I interferons and IL-6 also act on cells involved in antibody production. Somehow the immunologic tolerance to these cytokines is often spontaneously broken--even in healthy individuals. Thus, relatively high concentrations of high affinity IgG antibodies again...

    journal_title:Leukemia

    pub_type: 杂志文章,评审

    doi:

    authors: Hansen MB,Svenson M,Diamant M,Abell K,Bendtzen K

    更新日期:1995-07-01 00:00:00

  • Complex landscape of alternative splicing in myeloid neoplasms.

    abstract::Myeloid neoplasms are characterized by frequent mutations in at least seven components of the spliceosome that have distinct roles in the process of pre-mRNA splicing. Hotspot mutations in SF3B1, SRSF2, U2AF1 and loss of function mutations in ZRSR2 have revealed widely different aberrant splicing signatures with littl...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/s41375-020-1002-y

    authors: Hershberger CE,Moyer DC,Adema V,Kerr CM,Walter W,Hutter S,Meggendorfer M,Baer C,Kern W,Nadarajah N,Twardziok S,Sekeres MA,Haferlach C,Haferlach T,Maciejewski JP,Padgett RA

    更新日期:2020-08-04 00:00:00

  • Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signaling pathways and occurring concurrently: circulating cancer cells constitute an ideal target for concurrent treatment wi

    abstract::Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key role in homing and mobilization of hematopoietic progenitor (HPC) and hematopoietic cancer clonogenic cells (HCC). High expression of VLA-4 is required for homing of HPC and HCC, whereas downregulation of these molecules is required ...

    journal_title:Leukemia

    pub_type: 杂志文章,评审

    doi:10.1038/sj.leu.2403173

    authors: Gazitt Y

    更新日期:2004-01-01 00:00:00

  • Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes?

    abstract::Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I ...

    journal_title:Leukemia

    pub_type: 杂志文章,评审

    doi:10.1038/leu.2014.127

    authors: Balan A,Lucchini G,Schmidt S,Schneider A,Tramsen L,Kuçi S,Meisel R,Bader P,Lehrnbecher T

    更新日期:2014-10-01 00:00:00

  • Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1.

    abstract::Imatinib is usually a highly effective treatment for myeloproliferative neoplasms (MPNs) associated with ABL, PDGFRA or PDGFRB gene fusions; however, occasional imatinib-responsive patients have been reported without abnormalities of these genes. To identify novel imatinib-sensitive lesions, we screened 11 BCR-ABL-neg...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2008.295

    authors: Chase A,Schultheis B,Kreil S,Baxter J,Hidalgo-Curtis C,Jones A,Zhang L,Grand FH,Melo JV,Cross NC

    更新日期:2009-02-01 00:00:00

  • Significantly worse survival of patients with NIH-defined chronic graft-versus-host disease and thrombocytopenia or progressive onset type: results of a prospective study.

    abstract::Chronic graft-versus-host disease (GVHD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT). In 2005 the National Institutes of Health (NIH) established new criteria for chronic GVHD based on retrospective data and expert recommendations. We prospectively evaluated the incide...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2011.257

    authors: Kuzmina Z,Eder S,Böhm A,Pernicka E,Vormittag L,Kalhs P,Petkov V,Stary G,Nepp J,Knobler R,Just U,Krenn K,Worel N,Greinix HT

    更新日期:2012-04-01 00:00:00

  • Activating mutations of the c-kit proto-oncogene in a human mast cell leukemia cell line.

    abstract::The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in mast cell growth and differentiation. In a human mast cell leukemia cell line (HMC-1), KitR was found to be constitutively phosphorylated on tyrosine, activated and associated with phosphatidylinositol 3-kinase (P13K) i...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Kanakura Y,Furitsu T,Tsujimura T,Butterfield JH,Ashman LK,Ikeda H,Kitayama H,Kanayama Y,Matsuzawa Y,Kitamura Y

    更新日期:1994-04-01 00:00:00

  • The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells.

    abstract::The three DNA methyltransferase (DNMT)-inhibiting cytosine nucleoside analogues, azacitidine, decitabine and zebularine, which are currently studied as nonintensive therapy for myelodysplastic syndromes and acute myeloid leukemia (AML), differ in structure and metabolism, suggesting that they may have differential mol...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2008.397

    authors: Flotho C,Claus R,Batz C,Schneider M,Sandrock I,Ihde S,Plass C,Niemeyer CM,Lübbert M

    更新日期:2009-06-01 00:00:00

  • ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF.

    abstract::Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant m...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/s41375-018-0159-0

    authors: Triviai I,Zeschke S,Rentel J,Spanakis M,Scherer T,Gabdoulline R,Panagiota V,Thol F,Heuser M,Stocking C,Kröger N

    更新日期:2019-01-01 00:00:00

  • Establishment of multipotential and antigen presenting cell lines derived from myeloid leukemias in GM-CSF transgenic mice.

    abstract::In this study neonatal mice expressing a GM-CSF transgene (GMT mice), and their normal littermate controls, were infected with Moloney murine leukemia virus (MoMLV) to examine in vivo tumorigenesis. By 200 days, all of the GMT mice had died whereas median survival had not been reached in the littermates (P < 0.0003). ...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2400614

    authors: Rasko JE,Metcalf D,Alexander B,Strasser A,Begley CG

    更新日期:1997-05-01 00:00:00

  • Frequent elevation of Akt kinase phosphorylation in blood marrow and peripheral blood mononuclear cells from high-risk myelodysplastic syndrome patients.

    abstract::The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myeloid leukemia (AML). The progression of myelodysplastic s...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2404057

    authors: Nyåkern M,Tazzari PL,Finelli C,Bosi C,Follo MY,Grafone T,Piccaluga PP,Martinelli G,Cocco L,Martelli AM

    更新日期:2006-02-01 00:00:00

  • The retinoic acid alpha receptor gene is frequently disrupted in its 5' part in Chinese patients with acute promyelocytic leukemia.

    abstract::The t(15;17)(q22;q11-q21) translocation, a hallmark for acute promyelocytic leukemia (APL), has recently been shown to disrupt the retinoic acid-alpha receptor (RARA) gene localized on band 17q21. Leukemic cell DNAs from 16 Chinese patients with APL were analysed by Southern blot hybridization with probes covering the...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Chen Z,Chen SJ,Tong JH,Zhu YJ,Huang ME,Wang WC,Wu Y,Sun GL,Wang ZY,Larsen CJ

    更新日期:1991-04-01 00:00:00

  • Constitutive expression of GM-CSF mRNA by CML blast cells is correlated with endogenous megakaryocytic colony formation.

    abstract::Purified blast cells from peripheral blood of 12 patients, with chronic myelogenous leukemia (CML) in chronic phase, were analyzed for the constitutive expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) transcript. Seven out 12 patients exhibited the specific 1.0 kb GM-CSF mRNA. Six from these...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Lajmanovich A,Berthier R,Schweitzer A,Leger J,Hollard D

    更新日期:1993-08-01 00:00:00

  • DOCK2 interacts with FLT3 and modulates the survival of FLT3-expressing leukemia cells.

    abstract::The FMS-like tyrosine kinase-3 (FLT3) gene is the most commonly mutated gene in acute myeloid leukemia (AML), and patients carrying internal tandem duplication (ITD) mutations have a poor prognosis. Long-term inhibition of FLT3 activity in these patients has been elusive. To provide a more complete understanding of FL...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2016.284

    authors: Wu M,Hamaker M,Li L,Small D,Duffield AS

    更新日期:2017-03-01 00:00:00

  • A cell culture model for the treatment of acute myeloblastic leukemia with fludarabine and cytosine arabinoside.

    abstract::The purpose of this paper was to ascertain whether results obtained in cell cultures of AML clonogenic blast cells would provide a useful model for a clinical regimen that combines fludarabine (F-ara-AMP) and cytosine arabinoside (ara-C). In the cultures the nucleoside F-ara-A was used. Blast cells from the continuous...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Rayappa C,McCulloch EA

    更新日期:1993-07-01 00:00:00

  • Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97.

    abstract::In this study, the long-term outcome of 1818 patients treated in five consecutive clinical trials (the cooperative study group for childhood acute lymphoblastic leukaemia (COALL) 82, 85, 89, 92 and 97) from 24 cooperating centres in Germany is reported. The probability of event-free survival (pEFS) improved significan...

    journal_title:Leukemia

    pub_type: 临床试验,杂志文章

    doi:10.1038/leu.2009.249

    authors: Escherich G,Horstmann MA,Zimmermann M,Janka-Schaub GE,COALL study group.

    更新日期:2010-02-01 00:00:00

  • Establishment and characterization of a new human megakaryoblastic cell line (SET-2) that spontaneously matures to megakaryocytes and produces platelet-like particles.

    abstract::A new factor-independent megakaryoblastic cell line, designated SET-2, was established from the peripheral blood of a patient with leukemic transformation of essential thrombocythemia (ET). SET-2 expressed CD 4, 7, 13, 33, 34, 36, 38, 41, 61, 71, 117, 126, 130 and c-mpl. In addition, it spontaneously produced numerous...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2401608

    authors: Uozumi K,Otsuka M,Ohno N,Moriyama T,Suzuki S,Shimotakahara S,Matsumura I,Hanada S,Arima T

    更新日期:2000-01-01 00:00:00

  • Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data.

    abstract::Most modern treatment protocols for acute lymphoblastic leukaemia (ALL) include the analysis of minimal residual disease (MRD). To ensure comparable MRD results between different MRD-polymerase chain reaction (PCR) laboratories, standardization and quality control are essential. The European Study Group on MRD detecti...

    journal_title:Leukemia

    pub_type: 杂志文章,多中心研究

    doi:10.1038/sj.leu.2404586

    authors: van der Velden VH,Cazzaniga G,Schrauder A,Hancock J,Bader P,Panzer-Grumayer ER,Flohr T,Sutton R,Cave H,Madsen HO,Cayuela JM,Trka J,Eckert C,Foroni L,Zur Stadt U,Beldjord K,Raff T,van der Schoot CE,van Dongen JJ,Euro

    更新日期:2007-04-01 00:00:00

  • Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia.

    abstract::Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ prepar...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2404093

    authors: Ritter M,Kattmann D,Teichler S,Hartmann O,Samuelsson MK,Burchert A,Bach JP,Kim TD,Berwanger B,Thiede C,Jäger R,Ehninger G,Schäfer H,Ueki N,Hayman MJ,Eilers M,Neubauer A

    更新日期:2006-03-01 00:00:00

  • Donor leukemia following allogeneic bone marrow transplantation.

    abstract::Although allogeneic bone marrow transplantation has been shown to be a highly effective treatment for acute and chronic leukemia, leukemic relapse remains a significant problem. Leukemic relapse occurs in recipient cells in the majority of cases, but the paucity of donor cell leukemias may reflect the sensitivity of t...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Mc Cann SR,Lawler M,Gardiner N,O'Riordan J,Humphries P,De Arce M

    更新日期:1994-04-01 00:00:00

  • Absence of amplification of MDM2 gene, a regulator of p53 function, in myelodysplastic syndromes.

    abstract::The MDM2 gene is a gene whose product binds to p53 and regulates its function. Amplification of MDM2 has been found in human sarcomas, where it leads to inactivation of p53. In 64 cases of generally advanced myelodysplastic syndromes, we found no amplification or rearrangement of MDM2 gene by Southern analysis. MDM2 R...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Preudhomme C,Quesnel B,Vachee A,Lepelley P,Collyn-D'Hooghe M,Wattel E,Fenaux P

    更新日期:1993-08-01 00:00:00

  • JAK2V617F-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation.

    abstract::The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs, but the mechanism(s) responsible for MPN stem cell expansion remain in...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2016.114

    authors: Zhan H,Ma Y,Lin CH,Kaushansky K

    更新日期:2016-12-01 00:00:00

  • Proteomic analysis of childhood leukemia.

    abstract::Childhood acute lymphoblastic and myeloid leukemias are stratified into molecular and cytogenetic subgroups important for prognosis and therapy. Studies have shown that gene expression profiles can discriminate between leukemia subtypes. Thus, proteome analysis similarly holds the potential for characterizing differen...

    journal_title:Leukemia

    pub_type: 杂志文章,多中心研究

    doi:10.1038/sj.leu.2403897

    authors: Hegedus CM,Gunn L,Skibola CF,Zhang L,Shiao R,Fu S,Dalmasso EA,Metayer C,Dahl GV,Buffler PA,Smith MT

    更新日期:2005-10-01 00:00:00

  • Selected pharmacologic characteristics of idarubicin and idarubicinol.

    abstract::The pharmacology of ID and IDOL are of interest in light of the potential utility of ID in the treatment of adult and pediatric leukemia patients. Preclinical activity and cellular pharmacology of ID were suggestive of greater clinical activity when compared with several standard anthracyclines. Most intriguing were d...

    journal_title:Leukemia

    pub_type: 杂志文章,评审

    doi:

    authors: Ames MM,Spreafico F

    更新日期:1992-01-01 00:00:00

  • To be or not to be a T-lymphomas, that is determined by a dominant gene Tlsm-1 in mouse models.

    abstract::A single dominant gene Tlsm-1 was found to determine the type of spontaneous lymphomas to be T in the cross between AKR/Ms and SL/Kh. Microsatellite analysis mapped Tlsm-1 at the position 61 cM from centromere of Chr. 7. Study of this segment of T-lymphoma prone AKXD Rl strains also showed association of Tlsm-1 with T...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Hiai H,Yamada Y,Shisa H,Kamoto T,Abujiang P,Lu LM

    更新日期:1997-04-01 00:00:00

  • Essential thrombocythemia--clinical features, therapy and follow-up of 12 cases.

    abstract::The authors analyzed twelve patients with symptomatic essential throthrombocythemia (E.T.) diagnosed from 1983 to 1991. Haemorrhagic and thrombotic phenomena were the main presenting features. Treatment consisted mostly of alpha-interferon (IFN-alpha 2b) subcutaneously in dosage ranging from 3 to 5 MU/m2 and hydroxyur...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Lopes E,Ribeiro MM,Silva MJ,Gandra M,Principe F,Granato C

    更新日期:1992-01-01 00:00:00

  • p210 bcr-abl confers overexpression of inosine monophosphate dehydrogenase: an intrinsic pathway to drug resistance mediated by oncogene.

    abstract::The p210 bcr-abl fusion protein tyrosine kinase oncogene has been implicated in the pathogenesis of chronic granulocytic leukemia (CGL). Specific intracellular functions performed by p210 bcr-abl have recently been delineated. We considered the possibility that p210 bcr-abl may also regulate the abundance of inosine 5...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Gharehbaghi K,Burgess GS,Collart FR,Litz-Jackson S,Huberman E,Jayaram HN,Boswell HS

    更新日期:1994-08-01 00:00:00

  • Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia.

    abstract::It has been proposed that adoptive immunotherapy, for the treatment of relapsed AML, with cytotoxic T lymphocytes which show a relative specificity for the leukemic cells may have the advantage of maximizing the beneficial anti-leukemic effect whilst minimizing the probability of graft-versus-host disease. In this stu...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2402013

    authors: Woiciechowsky A,Regn S,Kolb HJ,Roskrow M

    更新日期:2001-02-01 00:00:00