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- Title
Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.
- Authors
Wang, Jing; Iwasaki, Hiromi; Krivtsov, Andrei; Febbo, Phillip G; Thorner, Aaron R; Ernst, Patricia; Anastasiadou, Ema; Kutok, Jeffery L; Kogan, Scott C; Zinkel, Sandra S; Fisher, Jill K; Hess, Jay L; Golub, Todd R; Armstrong, Scott A; Akashi, Koichi; Korsmeyer, Stanley J
- Abstract
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.
- Publication
The EMBO journal, 2005, Vol 24, Issue 2, p368
- ISSN
0261-4189
- Publication type
Journal Article
- DOI
10.1038/sj.emboj.7600521