BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4
BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4
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DOI：
10.1038/leu.2015.137
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发表时间：
2015-11-01
期刊：
影响因子：
11.4
通讯作者：
Kurokawa, M.
中科院分区：
文献类型：
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作者：
Morita, K.;Masamoto, Y.;Kurokawa, M.
尽管BAALC高表达是急性髓系白血病(AML)的不良预后因素，但BAALC导致白血病发生和耐药的确切机制以及针对BAALC高表达AML的治疗方法尚未完全阐明。在这项研究中，我们发现BAALC通过与支架蛋白MEK激酶-1(MEKK1)相互作用来维持细胞外信号调节激酶(ERK)的活性，从而诱导白血病细胞的细胞周期进展，而支架蛋白MEKK1抑制ERK与MAPKP3/DUSP6之间的相互作用。BAALC通过以ERK依赖的方式上调ATP结合盒蛋白来诱导AML细胞的化疗耐药，MEK抑制剂可以靶向于该蛋白。我们还证明，BAALC通过在胞浆中捕获Kruppel样因子4(KLF4)并抑制其在细胞核中的功能来阻断ERK介导的AML细胞的单核细胞分化。因此，MEK抑制治疗与KLF4诱导有协同作用，在体内外对高BAALC的AML细胞都是高效的。我们的数据为BAALC在调节AML细胞增殖和分化中的作用提供了分子基础，并强调了BAALC作为治疗BAALC-高AML的有吸引力的靶点的独特双重功能。
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 Kruppel-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.