title: Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through down-regulation of p19ARF.
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.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Nishimoto
authors.forename: Shunya
authors.initials: S
authors.lastname: Arai
authors.forename: Motoshi
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Goyama
authors.forename: Keiki
authors.initials: K
authors.lastname: Kumano
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kamikubo
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imai
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D016026:Bone Marrow Transplantation; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D015456:Leukemia, Biphenotypic, Acute / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000502:physiology; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D019941:Cyclin-Dependent Kinase Inhibitor p16; C425207:MLL-ENL oncoprotein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; C493726:Runx1 protein, mouse; D051788:Myeloid-Lymphoid Leukemia Protein