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    This document summarizes two studies related to multiple myeloma (MM). The first study finds that the AP-1 transcription factor JunB is induced in MM cells when co-cultured with bone marrow stromal cells through soluble factors like IL-6. Knockdown of JunB inhibits MM cell proliferation, suggesting it promotes MM pathogenesis. JunB knockdown also overcomes drug resistance. The second study finds that the protein DEPTOR is overexpressed during normal plasma cell differentiation from B cells. In MM cells, DEPTOR knockdown decreases markers of plasma cell maturation and reverts cells to a pre-plasma state, suggesting DEPTOR is important for plasma cell commitment. DEPT

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    This document summarizes two studies related to multiple myeloma (MM). The first study finds that the AP-1 transcription factor JunB is induced in MM cells when co-cultured with bone marrow stromal cells through soluble factors like IL-6. Knockdown of JunB inhibits MM cell proliferation, suggesting it promotes MM pathogenesis. JunB knockdown also overcomes drug resistance. The second study finds that the protein DEPTOR is overexpressed during normal plasma cell differentiation from B cells. In MM cells, DEPTOR knockdown decreases markers of plasma cell maturation and reverts cells to a pre-plasma state, suggesting DEPTOR is important for plasma cell commitment. DEPT

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    This document summarizes two studies related to multiple myeloma (MM). The first study finds that the AP-1 transcription factor JunB is induced in MM cells when co-cultured with bone marrow stromal cells through soluble factors like IL-6. Knockdown of JunB inhibits MM cell proliferation, suggesting it promotes MM pathogenesis. JunB knockdown also overcomes drug resistance. The second study finds that the protein DEPTOR is overexpressed during normal plasma cell differentiation from B cells. In MM cells, DEPTOR knockdown decreases markers of plasma cell maturation and reverts cells to a pre-plasma state, suggesting DEPTOR is important for plasma cell commitment. DEPT

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    30 views1 page

    tmpA7BF TMP

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    Frontiers
    This document summarizes two studies related to multiple myeloma (MM). The first study finds that the AP-1 transcription factor JunB is induced in MM cells when co-cultured with bone marrow stromal cells through soluble factors like IL-6. Knockdown of JunB inhibits MM cell proliferation, suggesting it promotes MM pathogenesis. JunB knockdown also overcomes drug resistance. The second study finds that the protein DEPTOR is overexpressed during normal plasma cell differentiation from B cells. In MM cells, DEPTOR knockdown decreases markers of plasma cell maturation and reverts cells to a pre-plasma state, suggesting DEPTOR is important for plasma cell commitment. DEPT

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    Abstracts

    delivery. SUV39H1 knock down inhibits H3K9me3, growth of


    myeloma cells, induces apoptosis, cell cycle deregulation and spontaneous accumulation of DNA double strand breaks. According to these
    results, SUV39H1 depletion sensitizes myeloma cells to melphalan.
    Chaetocin is a selective inhibitor of SUV39H1. We identied that
    chaetocin has anti-myeloma effects, at low nanomolar doses, on 11
    different myeloma cell lines, that are representative of the molecular
    heterogeneity of the patients, in association with H3K9 trimethylation
    inhibition. Furthermore, this signicant toxicity of chaetocin in MM
    was conrmed on primary myeloma cells of 5 patients cocultured with
    their bone marrow microenvironment without signicant toxicity on
    normal bone marrow cells and hematopoietic stem cells. Interestingly,
    the IC50 doses of chaetocin in MM were 50 fold lower compared to
    results published in AML, suggesting H3K9 HMTs could be a potent
    therapeutic target in MM.

    Moreover, GEP performed on inducible Tet-shJunB MM.1S cells cocultured with BMSCs suggested a key role for JunB in the regulation
    of Mcl-1 and c-Myc expression. Furthermore, knockdown of JunB
    overcame resistance of MM cells to dexamethasone. Conversely, 4OHT treatment of MM cell lines transduced with pMSCV-JunBER-IRES-GFP but not pMSCV-IRES-GFP induced signicant
    JunB/AP-1 luciferase activity and protected MM cells against bortezomib-induced apoptosis and ER stress. Ongoing experiments aim to
    conrm the in vivo relevance of our in vitro data in a MM xenograft
    mouse model inoculated with inducible Tet-shJunB MM.1S cells.
    Conclusion: Taken together, our data demonstrate for the rst time
    an important and surprising role of JunB/AP-1 in MM tumorigenesis
    and strongly propose it as a novel therapeutic target in MM.

    PO-233
    PO-232
    The AP-1 Transcription Factor JunB
    Promotes Multiple Myeloma (MM) Cell
    Proliferation, Survival and Drug Resistance
    in the Bone Marrow Microenvironment
    F. Fan,1 S. Vallet,1 M. Sattler,2 G. Tonon,3
    M.H. Bashari,1 L. Bakiri,4 M. Jarahian,5 A. Roccaro,2
    I. Ghobrial,2 C. Ball,5 H. Glimm,5 K.C. Anderson,2
    H. Goldschmidt,5 E.F. Wagner,4 D. Jaeger,1 K. Podar1
    1

    Medical Oncology, National Center for Tumor Diseases (NCT), Uni2

    versity of Heidelberg, Heidelberg, Germany; Department of Medical


    Oncology, Dana-Farber Cancer Institute, Boston, MA; 3San Raffaele
    Scientic Institute, Milan, Italy; 4Genes Development and Disease
    Group, Spanish National Cancer Research Centre, Madrid, Spain;
    5

    National Center for Tumor Diseases (NCT), University of Heidelberg,

    Heidelberg, Germany

    Introduction: The family of activator protein-1 (AP-1) transcription factors has been implicated in a multitude of physiologic processes,
    but also tumorigenesis. In multiple myeloma (MM), the role of AP-1 is
    largely unknown. Materials and Methods: MM cells were cocultured with primary bone marrow stromal cells (BMSCs) or BMSC
    lines. AP-1 expression was measured by western blot analysis and
    qPCR. To delineate the specic functional role of JunB in MM
    pathogenesis, we used knockdown and overexpression approaches
    followed by 3H-thymidine incorporation, ow cytometry and western blot analysis, as well as gene expression proling (GEP), and a
    MM xenograft mouse model. Results: Surprisingly, co-cultures of
    MM cells with BMSCs rapidly and strongly induced sustained
    expression of JunB, but not of other AP-1 family members. Induction
    of JunB is predominantly mediated by soluble factors (i.e IL-6)
    secreted by BMSCs rather than direct MM-BMSC contact. Pharmacologic inhibition identied the requirement of MEK/ERK and
    NF-kB for BMSC-induced JunB expression and AP-1 transcriptional
    activity. Functionally, signicant inhibition of proliferation was
    observed in MM cells carrying pLKO.1-JunB shRNA, but not
    pLKO.1-scrambled shRNA. In contrast, knockdown of other AP-1
    family members had minor effects on MM cell proliferation.

    A novel function of DEPTOR in


    multiple myeloma: commitment to
    plasma cell maturation
    D. Quwaider, A.B. Herrero, P. Krzeminski,
    L.A. Corchete, I. Misiewicz-Krzeminska,
    M.E. Sarasquete, J.J. Prez, N. Puig, R. Garca-Sanz,
    N.C. Gutirrez
    Hematology Department, University Hospital, IBSAL IBMCC (USALCSIC), Salamanca, Spain

    Funding: Asociacin Espaola Contra el Cncer (AECC:


    GCB120981SAN). Background: The understanding of plasma cell
    (PC) development could provide new insights for therapeutic strategies in MM. Here we explore the role of DEPTOR in the differentiation of B lymphocytes (BL) to PCs and its potential function
    in myeloma pathogenesis. Materials and methods: H929 and
    MM1S cell lines, and 10 healthy controls of bone marrow were
    included in the study. Cell sorting was used to isolate different B cell
    populations. mRNA expression was determined using microarrays
    (Human gene 2.0 ST array) and qRT-PCR, and protein levels were
    assessed by WB. Knockdown experiments were carried out using
    commercial siRNAs. Results: Previously published gene expression
    analysis by microarrays showed that DEPTOR was overexpressed in
    normal PC compared to normal BL (GSE6691 at GEO repository).
    This nding was conrmed by qRT-PCR. Thus, DEPTOR was
    signicantly overexpressed in PC (mean 2- CT, 0.05940.0574)
    compared to immature B cells (0.000900.00089), nave B cells
    (0.0012480.0011) and memory B cells (0.001450.00098)
    (P 0.001). To investigate the putative functional role of DEPTOR
    in MM, we carried out loss-of-function experiments in H929 and
    MM1S cell lines. Gene expression proling in H929 revealed
    decreased levels of CD38 and IRF4, and overexpression of PAX5 in
    DEPTOR-knockdown cells compared to control (q<0.05). Similar
    results were obtained by using qRT-PCR and Western blot.
    Knockdown of DEPTOR also resulted in an evident reduction in
    cell size and loss of endoplasmic reticulum expansion, further supporting the reversion of plasma cell state into pre-plasmablast.
    High levels of DEPTOR have been reported in some MM, especially
    in those carrying c-MAF/MAFB translocations. Here, we also investigated whether DEPTOR expression could be affected by deregulation

    15th International Myeloma Workshop, September 23-26, 2015

    - e215

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