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

Content Provider	PubMed Central
Author	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.
Copyright Year	2005
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 γ-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.
Related Links	http://dx.doi.org/10.1038/sj.emboj.7600521
Ending Page	381
Page Count	14
Starting Page	368
File Format	PDF
ISSN	02614189
e-ISSN	14602075
Journal	The EMBO Journal
Issue Number	2
Volume Number	24
Language	English
Publisher	Nature Publishing Group
Publisher Date	2005-01-26
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Immunology and Microbiology(all) Neuroscience(all) Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology and Microbiology Medicine Molecular Biology

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