Abstract:
:Myeloproliferative neoplasms with myelofibrosis (MPN-MF) demonstrate constitutive activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling that responds to treatment with the JAK1 and 2 kinase inhibitor (JAKi) ruxolitinib. However, MPN-MF often progresses (~20%) to secondary acute myeloid leukemia (sAML), where standard induction chemotherapy or ruxolitinib is relatively ineffective, necessitating the development of novel therapeutic approaches. In the present studies, we demonstrate that treatment with BET (bromodomain and extraterminal) protein inhibitor (BETi), for example, JQ1, inhibits growth and induces apoptosis of cultured and primary, patient-derived (PD), post-MPN sAML blast progenitor cells. Reverse-phase protein array, mass-cytometry and Western analyses revealed that BETi treatment attenuated the protein expressions of c-MYC, p-STAT5, Bcl-xL, CDK4/6, PIM1 and IL-7R, whereas it concomitantly induced the levels of HEXIM1, p21 and BIM in the sAML cells. Co-treatment with BETi and ruxolitinib synergistically induced apoptosis of cultured and PD sAML cells, as well as significantly improved survival of immune-depleted mice engrafted with human sAML cells. Although BETi or heat shock protein 90 inhibitor (HSP90i) alone exerted lethal activity, cotreatment with BETi and HSP90i was synergistically lethal against the ruxolitinib-persister or ruxolitinib-resistant sAML cells. Collectively, these findings further support in vivo testing of BETi-based combinations with JAKi and HSP90i against post-MPN sAML cells.
journal_name
Leukemiajournal_title
Leukemiaauthors
Saenz DT,Fiskus W,Manshouri T,Rajapakshe K,Krieger S,Sun B,Mill CP,DiNardo C,Pemmaraju N,Kadia T,Parmar S,Sharma S,Coarfa C,Qiu P,Verstovsek S,Bhalla KNdoi
10.1038/leu.2016.260subject
Has Abstractpub_date
2017-03-01 00:00:00pages
678-687issue
3eissn
0887-6924issn
1476-5551journal_volume
31pub_type
杂志文章相关文献
LEUKEMIA文献大全abstract::In B-CLL IgV(H) genes mutational status is a major prognostic factor. Since sequencing of IgV(H) genes is not available in most laboratories, an easily performed surrogate assay is desirable. To identify the best surrogate assay, and to better discriminate prognostic subgroups we analyzed clinical and biological data ...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2402780
更新日期:2003-01-01 00:00:00
abstract::Mutations of signal transducing molecules such as Ras have been shown to confer a growth advantage in leukaemic blasts and contribute to the pathogenesis of the disease. Alterations of signal transducing molecules other than Ras may play a role in leukaemogenesis. Knowledge of such mutations could also further our und...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1994-09-01 00:00:00
abstract::Outcomes after unmanipulated haploidentical stem cell transplantation (Haplo) and after unrelated cord blood transplantation (UCBT) are encouraging and have become alternative options to treat patients with high-risk acute leukemia without human leukocyte antigen (HLA) matched donor. We compared outcomes after UCBT an...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2015.98
更新日期:2015-09-01 00:00:00
abstract::APL-associated hemostasis disorders result from at least two distinct mechanisms due to the release of procoagulant activities and plasminogen activators from the leukemic cells. These two mechanisms (thrombin activation and plasmin activation) may cleave the fibrinogen molecule, but their respective roles in low fibr...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1995-01-01 00:00:00
abstract::In order to obtain more insight into the nature of the abnormal in vitro colony formation in myelodysplastic syndromes (MDS), we investigated the kinetics of the colony formation of 23 MDS cases in response to recombinant human interleukin-3 (IL-3), Granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyt...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1990-04-01 00:00:00
abstract::In a study carried out for patients receiving intrafamilial HLA-A,B,DR identical, MLC negative bone marrow transplants, RFLP profiles of HLA-class II for 27 donor recipient pairs were analyzed. Twenty-four pairs were found HLA-class II identical while three pairs were HLA-DP incompatible. The patients of these three p...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1990-03-01 00:00:00
abstract::In this study, we determined the respective roles of RelA and RelB NF-κB subunits in Epstein-Barr virus (EBV)-transformed B cells. Using different EBV-immortalized B-cell models, we showed that only RelA activation increased both survival and cell growth. RelB activity was induced secondarily to RelA activation and re...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2013.274
更新日期:2014-04-01 00:00:00
abstract::We have analyzed the expression of Tdt and CD7 in 335 cases of unequivocal acute myeloid leukemia (AML). Tdt was expressed in 80 (25%) of 321 evaluable cases. Twenty-six of 77 (34%) Tdt+ patients assessable for response, entered complete remission (CR) vs 121 of 209 (58%) Tdt- cases (P < 0.001). CD7 was expressed in 1...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2401067
更新日期:1998-07-01 00:00:00
abstract::The clinical, hematological, and cytogenetic data from two young adults with acute myeloid leukemia (AML) FAB type M1 is described. At diagnosis, cytogenetic investigation revealed the presence of the translocation t(6;9)(p23;q34). Bone marrow basophilia was not detected in either patient nor was there any evidence of...
journal_title:Leukemia
pub_type: 杂志文章,评审
doi:
更新日期:1993-04-01 00:00:00
abstract::Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduce...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2016.183
更新日期:2017-01-01 00:00:00
abstract::Fv-4 is a mouse gene that dominantly confers resistance to infection by ecotropic murine leukemia virus (MuLV). The Fv-4' env antigen that binds to the cell surface of Fv-4'-bearing C3H cells was found in sera from normal Fv-4'-bearing C4W mice. The serum Fv-4' env antigen binds to ecotropic MuLV receptors, shown by s...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1997-04-01 00:00:00
abstract::The fusion transcript AML1/ETO corresponding to translocation t(8;21)(q22;q22) can be found in approximately 7-12% of childhood de novo AML. Despite the favorable prognosis, some of these patients relapse. Most of MRD studies so far were performed on adults treated not uniformly. Therefore, we analyzed the follow-up o...
journal_title:Leukemia
pub_type: 杂志文章,多中心研究
doi:10.1038/sj.leu.2402959
更新日期:2003-06-01 00:00:00
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
更新日期:2006-02-01 00:00:00
abstract::Clonal chromosome abnormalities were detected in bone marrow cells of 20 patients with Fanconi anemia investigated at various stages of the disease. Two presented with acute leukemia, six with myelodysplastic syndrome, and 12 had minor or no morphological abnormalities of hematopoietic cells. Abnormalities of chromoso...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1996-11-01 00:00:00
abstract::Mutations of the GATA1 gene on chromosome X have been found in almost all cases of transient myeloproliferative disorder and acute megakaryoblastic leukemia (AMKL) accompanying Down syndrome (DS). Although most GATA1 mutations lead to the expression of GATA1s lacking the N-terminal activation domain, we recently found...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2404223
更新日期:2006-06-01 00:00:00
abstract::Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childh...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2401035
更新日期:1998-06-01 00:00:00
abstract::The combination of the anti-viral agents, zidovudine (AZT) and interferon-alpha (IFN), is a potent treatment of HTLV-I-associated adult T cell leukemia/lymphoma (ATL). In this study we investigate the possible mechanism of action of this combination by examining several cellular parameters including cell proliferation...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2401742
更新日期:2000-04-01 00:00:00
abstract::The chimeric fusion oncogene early B-cell factor 1-platelet-derived growth factor receptor-β (EBF1-PDGFRB) is a recurrent lesion observed in Philadelphia-like B-acute lymphoblastic leukemia (B-ALL) and is associated with particularly poor prognosis. While it is understood that this fusion activates tyrosine kinase sig...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2017.166
更新日期:2018-01-01 00:00:00
abstract::We studied changes in peripheral blood and bone marrow biopsy specimens obtained before, during, and after recombinant alpha 2b-interferon (IFN-alpha 2b) therapy in 25 patients with hairy cell leukemia. During therapy, only 1 patient showed no improvement in at least one of the parameters monitored. Granulocytopenia, ...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1987-04-01 00:00:00
abstract::The carcinoembryonic antigen (CEA) and the classical non-specific cross-reacting antigens (NCAs) belong to the CEA gene family which is part of the immunoglobulin superfamily. In normal hematopoiesis, CEA gene family members (CGMs) have only been reported on cells of myeloid and monocytic origin. In the present study,...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1994-12-01 00:00:00
abstract::Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated wit...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2403732
更新日期:2005-07-01 00:00:00
abstract::Mantle cell lymphoma represent a clinicopathologically distinct entity of malignant non-Hodgkin's lymphoma (NHL) and are characterized by a specific chromosomal translocation t(11;14)(q13;q32) involving the cyclin D1 gene also designated as bcl-1/PRAD1 gene on chromosome 11 and the heavy chain immunoglobulin joining r...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2401172
更新日期:1998-10-01 00:00:00
abstract::Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate ant...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/leu.2015.50
更新日期:2015-08-01 00:00:00
abstract::Employing a multicolour flow cytometry assay, 133 B-chronic lymphocytic leukaemia (B-CLL) cases were analysed for surface expression of CD38. Based on a cut-off value of 20%, CLL patients were categorised into a CD38-positive (> or = 20%, n = 56) and a CD38-negative subgroup (< 20%, n = 77) and separately analysed for...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2402339
更新日期:2002-01-01 00:00:00
abstract::A case of an infant male with Down's syndrome, pancytopenia, and a relative lymphocytosis is presented. A bone marrow aspirate and crushed marrow biopsy were evaluated by microscopy and flow cytometry. A population of immature lymphoid cells positive for CD10 (CALLA) and CD19 (Leu 12) was initially interpreted as sugg...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1993-11-01 00:00:00
abstract::max 41 transgenic mice consistently exhibit elevated numbers of mature granulocytes and monocytes in the peripheral blood and of immature and mature cells of these lineages in the marrow, spleen, lymph nodes and liver. The immature populations are not autonomous and exhibit a normal quantitative responsiveness to prol...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1996-02-01 00:00:00
abstract::The discovery of EGFR gene amplification in glioblastoma multiforme has prompted interest in experimental therapies to target the receptor on brain tumor cells. To develop an animal model for in vivo study of such strategies, we transfected C6 glioma cells with a plasmid containing the neomycin resistance gene and the...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1995-10-01 00:00:00
abstract::CD79 is a heterodimeric molecule comprising two polypeptide chains, B29 (CD79b) and mb-1 (CD79a). It is physically linked in the surface of B cells to membrane immunoglobulin, forming the B cell antigen receptor complex. Expression of the mb-1 (CD79a) chain has been studied in leukaemias and shown to be present in mos...
journal_title:Leukemia
pub_type: 杂志文章
doi:
更新日期:1996-05-01 00:00:00
abstract::Children of subcontinental (Indian and Pakistani) origin living in the United Arab Emirates (UAE) have previously been shown to have a higher relative frequency of ALL when compared to other ethnic groups. To analyze the possible effect of social class in this difference, a study of socioeconomic factors was conducted...
journal_title:Leukemia
pub_type: 杂志文章
doi:10.1038/sj.leu.2400601
更新日期:1997-04-01 00:00:00
abstract::Acute myeloid leukemia (AML) with minimal differentiation was usually referred to as acute undifferentiated leukemia in the past. With the help of immunophenotyping, this subtype of leukemia was shown to express myeloid antigens on the blasts and was designated AML-M0 by FAB Cooperative Study Group in 1991. Among the ...
journal_title:Leukemia
pub_type: 临床试验,杂志文章
doi:10.1038/sj.leu.2401521
更新日期:1999-10-01 00:00:00