BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4

K. Morita, Y. Masamoto, K. Kataoka, J. Koya, Y. Kagoya, H. Yashiroda, T. Sato, S. Murata, M. Kurokawa

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2248-2256
Number of pages9
Issue number11
Publication statusPublished - 2015 Nov 1
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research


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