title: BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4.
abstract: Although high brain and acute leukemia, cytoplasmic (BAALC) expression is a well-characterized poor prognostic factor in acute myeloid leukemia (AML), neither the exact mechanisms by which BAALC drives leukemogenesis and drug resistance nor therapeutic approaches against BAALC-high AML have been properly elucidated. In this study, we found that BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MEK kinase-1 (MEKK1), which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6). BAALC conferred chemoresistance in AML cells by upregulating ATP-binding cassette proteins in an ERK-dependent manner, which can be therapeutically targeted by MEK inhibitor. We also demonstrated that BAALC blocks ERK-mediated monocytic differentiation of AML cells by trapping Krüppel-like factor 4 (KLF4) in the cytoplasm and inhibiting its function in the nucleus. Consequently, MEK inhibition therapy synergizes with KLF4 induction and is highly effective against BAALC-high AML cells both in vitro and in vivo. Our data provide a molecular basis for the role of BAALC in regulating proliferation and differentiation of AML cells and highlight the unique dual function of BAALC as an attractive therapeutic target against BAALC-high AML.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Morita
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Masamoto
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Koya
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kagoya
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yashiroda
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Transfusion Medicine, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.affiliation: Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.identifier: http://orcid.org/0000-0002-3177-3503
authors.initials: S
authors.lastname: Murata
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Cell Therapy and Transplantation, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D048728:MAP Kinase Kinase Kinase 1 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D009363:Neoplasm Proteins / Q000502:physiology*; D011485:Protein Binding
chemical_list: C442828:BAALC protein, human; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human