JunB Protects against Myeloid Malignancies by Limiting Hematopoietic Stem Cell Proliferation and Differentiation without Affecting Self-Renewal

被引:114
作者
Santaguida, Marianne [1 ]
Schepers, Koen [1 ]
King, Bryan [1 ]
Sabnis, Amit J. [2 ]
Forsberg, E. Camilla [3 ]
Attema, Joanne L. [4 ]
Braun, Benjamin S. [2 ]
Passegue, Emmanuelle [1 ]
机构
[1] Univ Calif San Francisco, Dept Med, Div Hematol Oncol, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
[3] Univ Calif Santa Cruz, Inst Biol Stem Cells, Santa Cruz, CA 95064 USA
[4] Lund Univ, Inst Expt Med Sci, S-22184 Lund, Sweden
关键词
TGF-BETA; GENE-EXPRESSION; IN-VIVO; LEUKEMIA; MAINTENANCE; NOTCH; PROGENITORS; P16(INK4A); NICHES;
D O I
10.1016/j.ccr.2009.02.016
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Loss of the JunB/AP-1 transcription factor induces a myeloproliferative disease (MPD) arising from the hematopoietic stem cell (HSC) compartment. Here, we show that junB inactivation deregulates the cell-cycle machinery and increases the proliferation of long-term repopulating HSCs (LT-HSCs) without impairing their self-renewal or regenerative potential in vivo. We found that JunB loss destabilizes a complex network of genes and pathways that normally limit myeloid differentiation, leading to impaired responsiveness to both Notch and TGF-beta signaling due in part to transcriptional deregulation of the Hes1 gene. These results demonstrate that LT-HSC proliferation and differentiation are uncoupled from self-renewal and establish some of the mechanisms by which JunB normally limits the production of myeloid progenitors, hence preventing initiation of myeloid malignancies.
引用
收藏
页码:341 / 352
页数:12
相关论文
共 31 条
[1]   Hematopoietic stem cell self-renewal [J].
Akala, Omobolaji O. ;
Clarke, Michael F. .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2006, 16 (05) :496-501
[2]   Cell cycle promoting activity of JunB through cyclin A activation [J].
Andrecht, S ;
Kolbus, A ;
Hartenstein, B ;
Angel, P ;
Schorpp-Kistner, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (39) :35961-35968
[3]   Cell cycle-dependent variations in c-Jun and JunB phosphorylation: a role in the control of cyclin D1 expression [J].
Bakiri, L ;
Lallemand, D ;
Bossy-Wetzel, E ;
Yaniv, M .
EMBO JOURNAL, 2000, 19 (09) :2056-2068
[4]   Signaling pathways governing stem-cell fate [J].
Blank, Ulrika ;
Karlsson, Goeran ;
Karlsson, Stefan .
BLOOD, 2008, 111 (02) :492-503
[5]   Cross-talk between the Notch and TGF-β signaling pathways mediated by interaction of the Notch intracellular domain with Smad3 [J].
Blokzijl, A ;
Dahlqvist, C ;
Reissmann, E ;
Falk, A ;
Moliner, A ;
Lendahl, U ;
Ibáñez, CF .
JOURNAL OF CELL BIOLOGY, 2003, 163 (04) :723-728
[6]   In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells [J].
Cheshier, SP ;
Morrison, SJ ;
Liao, XS ;
Weissman, IL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (06) :3120-3125
[7]   Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance [J].
Duncan, AW ;
Rattis, FM ;
DiMascio, LN ;
Congdon, KL ;
Pazianos, G ;
Zhao, C ;
Yoon, K ;
Cook, JM ;
Willert, K ;
Gaiano, N ;
Reya, T .
NATURE IMMUNOLOGY, 2005, 6 (03) :314-322
[8]   New evidence supporting megakaryocyte-erythrocyte potential of Flk2/Flt3+ multipotent hematopoietic progenitors [J].
Forsberg, E. Camilla ;
Serwold, Thomas ;
Kogan, Scott ;
Weissman, Irving L. ;
Passegue, Emmanuelle .
CELL, 2006, 126 (02) :415-426
[9]   Isolation of a highly quiescent subpopulation of primitive leukemic cells in chronic myeloid leukemia [J].
Holyoake, T ;
Jiang, XY ;
Eaves, C ;
Eaves, A .
BLOOD, 1999, 94 (06) :2056-2064
[10]   Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a [J].
Janzen, Viktor ;
Forkert, Randolf ;
Fleming, Heather E. ;
Saito, Yoriko ;
Waring, Michael T. ;
Dombkowski, David M. ;
Cheng, Tao ;
DePinho, Ronald A. ;
Sharpless, Norman E. ;
Scadden, David T. .
NATURE, 2006, 443 (7110) :421-426