title: Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells.
abstract: RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of Runx1/Cbfb inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins.
authors: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors: Susumu
authors: S
authors: Goyama
authors: Janet
authors: J
authors: Schibler
authors: Lea
authors: L
authors: Cunningham
authors: Yue
authors: Y
authors: Zhang
authors: Yalan
authors: Y
authors: Rao
authors: Nahoko
authors: N
authors: Nishimoto
authors: Masahiro
authors: M
authors: Nakagawa
authors: Andre
authors: A
authors: Olsson
authors: Mark
authors: M
authors: Wunderlich
authors: Kevin A
authors: KA
authors: Link
authors: Benjamin
authors: B
authors: Mizukawa
authors: H Leighton
authors: HL
authors: Grimes
authors: Mineo
authors: M
authors: Kurokawa
authors: P Paul
authors: PP
authors: Liu
authors: Gang
authors: G
authors: Huang
authors: James C
authors: JC
authors: Mulloy
mesh_terms: D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism / Q000502:physiology*; D050658:Core Binding Factor beta Subunit / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D020125:Mutation, Missense; D022423:Myeloid Cells / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein
chemical_list: C107844:AML1-ETO fusion protein, human; C493692:CBFB protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; C474558:MLL-AF9 fusion protein, human; D015514:Oncogene Proteins, Fusion; D019253:Proto-Oncogene Proteins c-bcl-2; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein
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