Abstract
Dysfunction of AML1/Runx1, a transcription factor, plays a crucial role in the development of many types of leukemia. Additional events are often required for AML1 dysfunction to induce full-blown leukemia; however, a mechanistic basis of their cooperation is still elusive. Here, we investigated the effect of AML1 deficiency on the development of MLL-ENL leukemia in mice. Aml1 excised bone marrow cells lead to MLL-ENL leukemia with shorter duration than Aml1 intact cells in vivo. Although the number of MLL-ENL leukemia-initiating cells is not affected by loss of AML1, the proliferation of leukemic cells is enhanced in Aml1-excised MLL-ENL leukemic mice. We found that the enhanced proliferation is the result of repression of p19(ARF) that is directly regulated by AML1 in MLL-ENL leukemic cells. We also found that down-regulation of p19(ARF) induces the accelerated onset of MLL-ENL leukemia, suggesting that p19(ARF) is a major target of AML1 in MLL-ENL leukemia. These results provide a new insight into a role for AML1 in the progression of leukemia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / genetics
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Bone Marrow Transplantation
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Core Binding Factor Alpha 2 Subunit / biosynthesis
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Core Binding Factor Alpha 2 Subunit / deficiency
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / physiology*
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Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / physiology
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Female
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Gene Expression Regulation, Leukemic / genetics*
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Leukemia, Biphenotypic, Acute / genetics*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / physiology
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Neoplastic Stem Cells / transplantation
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology
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Radiation Chimera
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Recombinant Fusion Proteins / physiology
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Transcription, Genetic
Substances
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Apoptosis Regulatory Proteins
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Cdkn2a protein, mouse
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Cell Cycle Proteins
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Core Binding Factor Alpha 2 Subunit
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Cyclin-Dependent Kinase Inhibitor p16
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MLL-ENL oncoprotein, human
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Recombinant Fusion Proteins
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Runx1 protein, mouse
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Myeloid-Lymphoid Leukemia Protein