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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.
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页码:368 / 381
页数:14
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