Transcriptomics

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Transcription profiling of mouse MLL-CBP line to assess the immediate effects of induced MLL-CBP expression on hematopoiesis


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 knock-in 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 (RNAi) demonstrated that MLL-CBP required Hox a9 for its enhanced cell expansion. Following exposure to sublethal g-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 (t-AMML)/chronic myelomonocytic leukemia (t-CMML)/myelodysplastic/myeloproliferative disorder (t-MD/MPD) 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.

INSTRUMENT(S): 418 [Affymetrix]

ORGANISM(S): Mus musculus  

DISEASE(S): Myeloid Neoplasm

SUBMITTER: Stanley J Korsmeyer  

PROVIDER: E-MEXP-213 | ArrayExpress | 2005-01-01

REPOSITORIES: ArrayExpress

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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-  ...[more]

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