Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease.
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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. |
Year of Publication | 2005
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Journal | EMBO J
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Volume | 24
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Issue | 2
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Pages | 368-81
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Date Published | 2005 Jan 26
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ISSN | 0261-4189
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DOI | 10.1038/sj.emboj.7600521
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PubMed ID | 15635450
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PubMed Central ID | PMC545811
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Grant list | P01 CA068484 / CA / NCI NIH HHS / United States
P01 DK050654 / DK / NIDDK NIH HHS / United States
CA68484 / CA / NCI NIH HHS / United States
DK50654 / DK / NIDDK NIH HHS / United States
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