KUKU

KU ScholarWorks

  • myKU
  • Email
  • Enroll & Pay
  • KU Directory
    • Login
    View Item 
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    •   KU ScholarWorks
    • Dissertations and Theses
    • Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Genetic alterations in Adult T cell leukemia

    Thumbnail
    View/Open
    Yeh_ku_0099D_15630_DATA_1.pdf (4.513Mb)
    Issue Date
    2017-12-31
    Author
    Yeh, Chien-Hung
    Publisher
    University of Kansas
    Format
    223 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pathology & Laboratory Medicine
    Rights
    Copyright held by the author.
    Metadata
    Show full item record
    Abstract
    Human T-cell leukemia virus type 1 (HTLV-1), which infects more than 20 million people worldwide, is known to cause adult T-cell leukemia (ATL). Even those patients treated with intense chemotherapy have a poor prognosis [1]. Although the detailed mechanisms on how HTLV-1 transforms T cells are unclear, it is believed that the viral oncoprotein Tax and the accumulation of somatic alterations lead to ATL [2]. In 2015, Seishi Ogawa and colleague used whole-exome sequencing and whole-genome sequencing to comprehensively analyze ATL genetic alterations [2, 3]. They found that fifty genes are significantly mutated, with 13 genes (PLCG1, PRKCB, CCR4, CARD11, STAT3, TP53, VAV1, TBL1XR1, NOTCH1, GATA3, IRF4, FAS, CCR7) affecting more than 10% of ATL patients [2]. In our previous study, we found Notch1 mutations in 30% of ATL patients leading to reduced Fbw7-mediated degradation and stabilization of the intracellular cleaved form of Notch1 (ICN1). In addition, Notch inhibitors reduced ATL tumor formation in a xenograft model [4]. Since FBXW7 has been reported to be mutated in 6% of human tumors, we hypothesized that the deregulation of FBXW7 can accelerate ATL proliferation and transformation. In my first study, we found that FBXW7 is down-regulated and mutated in ATL patients. In contrast to the tumor suppressor role of FBXW7 wild-type, FBXW7 D510E increased cell proliferation and transformation both in vitro and in an ATL xenograft model [5]. Genome-wide H3K27 me3 accumulation has been observed in ATL patients, which can be explained by Polycomb repressive complex 2 hyperactivation [6]. In addition, EZH2 suppressed Fbxw7 expression via H3K27me3, resulting in Notch activation [7]. We hypothesized that the mutations of epigenetic regulators can reduce the FBXW7 expression in ATL. In my second study, we applied whole-genome next-generation sequencing (NGS) of uncultured freshly isolated ATL samples and identified the presence of mutations in SUZ12, DNMT1, DNMT3A, DNMT3B, TET1, TET2, IDH1, IDH2, MLL, MLL2, MLL3 and MLL4. TET2 was the most frequently mutated gene, occurring in 32 % (10/31) of ATL samples analyzed. Consistent with the previous report, Seishi Ogawa demonstrated hypermethylation in promoter-associated CpG islands in ATL [2]. Since the FBXW7 promoter hypermethylation has been reported [8] and a DNA methyltransferase inhibitor can restore the expression of FBXW7, the correlation of TET2 mutations and FBXW7 down-regulation needs to be further examined. FBXW7α R465C/+ knockin mice increased T-ALL formation when in cooperation with a Notch1 mutation [9]. Mechanically, FBXW7α R465C/+ stabilized c-Myc protein half-life, therefore increasing leukemia-initiating cells (LICs) in FBXW7α R465C/+ knockin mice [9]. In my third study, we confirmed the existence of side populations having both self-renewal and leukemia-renewal capacity and representing cancer stem cells (CSC)/ leukemia-initiating cells (LIC) in ATL cell lines and patient samples. We further show that PI3K and the NOTCH1 signaling pathway have opposite functions on the ATL side population. Constitutive activation of NOTCH1 signaling depletes the pool of side population cells in ATL-derived cell lines. Since Notch1 signaling is deregulated and essential for ATL progression, our results indicate another mechanism to explain how Notch1 signaling is constitutively active in ATL patients, implying a unique therapeutic opportunity to target FBXW7 in the future.
    URI
    http://hdl.handle.net/1808/27047
    Collections
    • Dissertations [3959]

    Items in KU ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.


    We want to hear from you! Please share your stories about how Open Access to this item benefits YOU.


    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    Browse

    All of KU ScholarWorksCommunities & CollectionsThis Collection

    My Account

    LoginRegister

    Statistics

    View Usage Statistics

    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

    The University of Kansas
      Contact KU ScholarWorks
    Lawrence, KS | Maps
     
    • Academics
    • Admission
    • Alumni
    • Athletics
    • Campuses
    • Giving
    • Jobs

    The University of Kansas prohibits discrimination on the basis of race, color, ethnicity, religion, sex, national origin, age, ancestry, disability, status as a veteran, sexual orientation, marital status, parental status, gender identity, gender expression and genetic information in the University’s programs and activities. The following person has been designated to handle inquiries regarding the non-discrimination policies: Director of the Office of Institutional Opportunity and Access, IOA@ku.edu, 1246 W. Campus Road, Room 153A, Lawrence, KS, 66045, (785)864-6414, 711 TTY.

     Contact KU
    Lawrence, KS | Maps