https://scholars.lib.ntu.edu.tw/handle/123456789/631239
標題: | Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia | 作者: | Sahoo, Binay K Lin, Yuh-Charn Tu, Cheng-Fen CHIEN-CHIN LIN Liao, Wei-Ju Li, Fu-An Li, Ling-Hui Mou, Kurt Yun Roffler, Steve R Wang, Shu-Ping Yeh, Chi-Tai CHI-YUAN YAO HSIN-AN HOU WEN-CHIEN CHOU HWEI-FANG TIEN Yang, Ruey-Bing |
公開日期: | 1-五月-2023 | 卷: | 108 | 期: | 5 | 來源出版物: | Haematologica | 摘要: | A hallmark of mixed lineage leukemia gene-rearranged (MLL-r) acute myeloid leukemia that offers an opportunity for targeted therapy is addiction to protein tyrosine kinase signaling. One such signal is the receptor tyrosine kinase Fms-like receptor tyrosine kinase 3 (FLT3) upregulated by cooperation of the transcription factors homeobox A9 (HOXA9) and Meis homeobox 1 (MEIS1). Signal peptide-CUB-EGF-like repeat-containing protein (SCUBE) family proteins have previously been shown to act as a co-receptor for augmenting signaling activity of a receptor tyrosine kinase (e.g., vascular endothelial growth factor receptor). However, whether SCUBE1 is involved in the pathological activation of FLT3 during MLL-r leukemogenesis remains unknown. Here we first show that SCUBE1 is a direct target of HOXA9/MEIS1 that is highly expressed on the MLL-r cell surface and predicts poor prognosis in de novo acute myeloid leukemia. We further demonstrate, by using a conditional knockout mouse model, that Scube1 is required for both the initiation and maintenance of MLL-AF9-induced leukemogenesis in vivo. Further proteomic, molecular and biochemical analyses revealed that the membrane-tethered SCUBE1 binds to the FLT3 ligand and the extracellular ligand-binding domains of FLT3, thus facilitating activation of the signal axis FLT3-LYN (a non-receptor tyrosine kinase) to initiate leukemic growth and survival signals. Importantly, targeting surface SCUBE1 by an anti-SCUBE1 monomethyl auristatin E antibody-drug conjugate led to significantly decreased cell viability specifically in MLL-r leukemia. Our study indicates a novel function of SCUBE1 in leukemia and unravels the molecular mechanism of SCUBE1 in MLL-r acute myeloid leukemia. Thus, SCUBE1 is a potential therapeutic target for treating leukemia caused by MLL rearrangements. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/631239 | ISSN: | 03906078 | DOI: | 10.3324/haematol.2022.281151 |
顯示於: | 醫學院附設醫院 (臺大醫院) |
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