Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease

被引:85
作者
Wang, J
Iwasaki, H
Krivtsov, A
Febbo, PG
Thorner, AR
Ernst, P
Anastasiadou, E
Kutok, JL
Kogan, SC
Zinkel, SS
Fisher, JK
Hess, JL
Golub, TR
Armstrong, SA
Akashi, K
Korsmeyer, SJ
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst,Dept Pathol & Med, Boston, MA 02115 USA
[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA
[3] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA
[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Harvard Inst Med, Boston, MA USA
[6] Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA
[7] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA
[8] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
关键词
granulocyte/macrophage progenitors; leukemogenesis; MLL-CBP; myeloproliferative disease;
D O I
10.1038/sj.emboj.7600521
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Chromosomal translocations that fuse the mixed lineage leukemia (MLL) gene with multiple partners typify acute leukemias of infancy as well as therapy-related leukemias. We utilized a conditional knockin strategy to bypass the embryonic lethality caused by MLL-CBP expression and to assess the immediate effects of induced MLL-CBP expression on hematopoiesis. Within days of activating MLL-CBP, the fusion protein selectively expanded granulocyte/macrophage progenitors (GMP) and enhanced their self-renewal/proliferation. MLL-CBP altered the gene expression program of GMP, upregulating a subset of genes including Hox a9. Inhibition of Hox a9 expression by RNA interference demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal gamma-irradiation or N-ethyl-N-nitrosourea (ENU), MLL-CBP mice developed myelomonocytic hyperplasia and progressed to fatal myeloproliferative disorders. These represented the spectrum of therapy-induced acute myelomonocytic leukemia/chronic myelomonocytic leukemia/myelodysplastic/myeloproliferative disorder similar to that seen in humans possessing the t(11;16). This model of MLL-CBP therapy-related myeloproliferative disease demonstrates the selectivity of this MLL fusion for GMP cells and its ability to initiate leukemogenesis in conjunction with cooperating mutations.
引用
收藏
页码:368 / 381
页数:14
相关论文
共 44 条
[1]   MEIS1 and HOXA7 genes in human acute myeloid leukemia [J].
Afonja, O ;
Smith, JE ;
Cheng, DM ;
Goldenberg, AS ;
Amorosi, E ;
Shimamoto, T ;
Nakamura, S ;
Ohyashiki, K ;
Ohyashiki, J ;
Toyama, K ;
Takeshita, K .
LEUKEMIA RESEARCH, 2000, 24 (10) :849-855
[2]   MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia [J].
Armstrong, SA ;
Staunton, JE ;
Silverman, LB ;
Pieters, R ;
de Boer, ML ;
Minden, MD ;
Sallan, SE ;
Lander, ES ;
Golub, TR ;
Korsmeyer, SJ .
NATURE GENETICS, 2002, 30 (01) :41-47
[3]   Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9 [J].
Ayton, PM ;
Cleary, ML .
GENES & DEVELOPMENT, 2003, 17 (18) :2298-2307
[4]   The CBP co-activator is a histone acetyltransferase [J].
Bannister, AJ ;
Kouzarides, T .
NATURE, 1996, 384 (6610) :641-643
[5]   Rearrangement of the MLL gene confers a poor prognosis in childhood acute lymphoblastic leukemia, regardless of presenting age [J].
Behm, FG ;
Raimondi, SC ;
Frestedt, JL ;
Liu, Q ;
Crist, WM ;
Downing, JR ;
Rivera, GK ;
Kersey, JH ;
Pui, CH .
BLOOD, 1996, 87 (07) :2870-2877
[6]   CREB-binding protein cooperates with transcription factor GATA-1 and is required for erythroid differentiation [J].
Blobel, GA ;
Nakajima, T ;
Eckner, R ;
Montminy, M ;
Orkin, SH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (05) :2061-2066
[7]   The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9 [J].
Borrow, J ;
Shearman, AM ;
Stanton, VP ;
Becher, R ;
Collins, T ;
Williams, AJ ;
Dube, I ;
Katz, F ;
Kwong, YL ;
Morris, C ;
Ohyashiki, K ;
Toyama, K ;
Rowley, J ;
Housman, DE .
NATURE GENETICS, 1996, 12 (02) :159-167
[8]   Regulation of activity of the transcription factor GATA-1 by acetylation [J].
Boyes, J ;
Byfield, P ;
Nakatani, Y ;
Ogryzko, V .
NATURE, 1998, 396 (6711) :594-598
[9]   VERY HIGH-FREQUENCY OF LYMPHOMA INDUCTION BY A CHEMICAL CARCINOGEN IN PIM-1 TRANSGENIC MICE [J].
BREUER, M ;
SLEBOS, R ;
VERBEEK, S ;
VANLOHUIZEN, M ;
WIENTJENS, E ;
BERNS, A .
NATURE, 1989, 340 (6228) :61-63
[10]   EVI-2, A COMMON INTEGRATION SITE INVOLVED IN MURINE MYELOID LEUKEMOGENESIS [J].
BUCHBERG, AM ;
BEDIGIAN, HG ;
JENKINS, NA ;
COPELAND, NG .
MOLECULAR AND CELLULAR BIOLOGY, 1990, 10 (09) :4658-4666