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EMBO J DOI:10.1038/sj.emboj.7600521

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

Publication TypeJournal Article
Year of Publication2005
AuthorsWang, 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
JournalEMBO J
Volume24
Issue2
Pages368-81
Date Published2005 Jan 26
ISSN0261-4189
KeywordsAnimals, CREB-Binding Protein, DNA-Binding Proteins, Histone-Lysine N-Methyltransferase, Mice, Molecular Sequence Data, Myeloid-Lymphoid Leukemia Protein, Myeloproliferative Disorders, Nuclear Proteins, Proto-Oncogenes, Reverse Transcriptase Polymerase Chain Reaction, Trans-Activators, Transcription Factors
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.

URLhttp://dx.doi.org/10.1038/sj.emboj.7600521
DOI10.1038/sj.emboj.7600521
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/15635450?dopt=Abstract

Alternate JournalEMBO J.
PubMed ID15635450
PubMed Central IDPMC545811
Grant ListP01 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