TY - JOUR AU - Sahoo, Binay K. AU - Lin, Yuh-Charn AU - Tu, Cheng-Fen AU - Lin, Chien-Chin AU - Liao, Wei-Ju AU - Li, Fu-An AU - Li, Ling-Hui AU - Mou, Kurt Yun AU - Roffler, Steve R. AU - Wang, Shu-Ping AU - Yeh, Chi-Tai AU - Yao, Chi-Yuan AU - Hou, Hsin-An AU - Chou, Wen-Chien AU - Tien, Hwei-Fang AU - Yang, Ruey-Bing PY - 2023/05/01 Y2 - 2024/03/28 TI - Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia JF - Haematologica JA - haematol VL - 108 IS - 5 SE - Articles DO - 10.3324/haematol.2022.281151 UR - https://haematologica.org/article/view/haematol.2022.281151 SP - 1284-1299 AB - 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. ER -