Abstract
The inv(16) is one of the most frequent chromosomal translocations associated with acute myeloid leukemia (AML) and creates a chimeric fusion protein consisting of most of the runt-related X1 co-factor, core binding factor beta fused to the smooth muscle myosin heavy chain MYH11. Expression of the ARF tumor suppressor is regulated by runt-related X1, suggesting that the inv(16) fusion protein (IFP) may repress ARF expression. We established a murine bone marrow transplant model of the inv(16) in which wild type, Arf+/-, and Arf-/- bone marrow were engineered to express the IFP. IFP expression was sufficient to induce a myelomonocytic AML even when expressed in wild type bone marrow, yet removal of only a single allele of Arf greatly accelerated the disease, indicating that Arf is haploinsufficient for the induction of AML in the presence of the inv(16).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Animals
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Bone Marrow Cells / cytology
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Bone Marrow Transplantation
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Cyclin-Dependent Kinase Inhibitor p16
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DNA / metabolism
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Flow Cytometry
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Genes, Reporter
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Green Fluorescent Proteins / metabolism
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Humans
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Leukemia, Myeloid, Acute / genetics*
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Leukemia, Myeloid, Acute / metabolism
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Liver / metabolism
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Mice
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Mice, Transgenic
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Mutagenesis
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NIH 3T3 Cells
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Oncogene Proteins, Fusion / metabolism
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Oncogene Proteins, Fusion / physiology*
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Plasmids / metabolism
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Promoter Regions, Genetic
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Protein Binding
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Recombinant Fusion Proteins / chemistry
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Spleen / metabolism
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Time Factors
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Transfection
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Translocation, Genetic
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Tumor Suppressor Protein p14ARF / genetics*
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Tumor Suppressor Protein p14ARF / metabolism
Substances
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Cdkn2a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Oncogene Proteins, Fusion
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p14ARF
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inv(16) fusion protein, human
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Green Fluorescent Proteins
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DNA