Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica; Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei.
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei.
Haematologica. 2023 May 1;108(5):1284-1299. doi: 10.3324/haematol.2022.281151.
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.
一个混合谱系白血病基因重排(MLL-r)急性髓系白血病的标志,为靶向治疗提供了机会,是对蛋白酪氨酸激酶信号的依赖。其中一种信号是受转录因子同源盒 A9(HOXA9)和Meis 同源盒 1(MEIS1)合作上调的受体酪氨酸激酶 Fms 样受体酪氨酸激酶 3(FLT3)。先前已经表明信号肽-CUB-EGF 样重复蛋白(SCUBE)家族蛋白作为共受体,可增强受体酪氨酸激酶(例如血管内皮生长因子受体)的信号活性。然而,SCUBE1 是否参与 MLL-r 白血病发生过程中的 FLT3 病理性激活仍不清楚。在这里,我们首先表明 SCUBE1 是 HOXA9/MEIS1 的直接靶标,在 MLL-r 细胞表面高度表达,并预测初发性急性髓系白血病的预后不良。我们进一步通过使用条件性敲除小鼠模型证明,Scube1 对于体内 MLL-AF9 诱导的白血病发生的起始和维持都是必需的。进一步的蛋白质组学、分子和生化分析表明,膜结合的 SCUBE1 与 FLT3 配体和 FLT3 的细胞外配体结合域结合,从而促进信号轴 FLT3-LYN(一种非受体酪氨酸激酶)的激活,以启动白血病生长和存活信号。重要的是,通过针对表面 SCUBE1 的抗 SCUBE1 单甲基奥瑞他汀 E 抗体药物偶联物进行靶向治疗,特异性地导致 MLL-r 白血病细胞活力显著降低。我们的研究表明了 SCUBE1 在白血病中的新功能,并揭示了 SCUBE1 在 MLL-r 急性髓系白血病中的分子机制。因此,SCUBE1 是治疗由 MLL 重排引起的白血病的潜在治疗靶点。