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Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia
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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153537/ https://www.ncbi.nlm.nih.gov/pubmed/36005562 http://dx.doi.org/10.3324/haematol.2022.281151 |
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author | Sahoo, Binay K. Lin, Yuh-Charn Tu, Cheng-Fen Lin, Chien-Chin Liao, Wei-Ju Li, Fu-An Li, Ling-Hui Mou, Kurt Yun Roffler, Steve R. Wang, Shu-Ping Yeh, Chi-Tai Yao, Chi-Yuan Hou, Hsin-An Chou, Wen-Chien Tien, Hwei-Fang Yang, Ruey-Bing |
author_facet | Sahoo, Binay K. Lin, Yuh-Charn Tu, Cheng-Fen Lin, Chien-Chin Liao, Wei-Ju Li, Fu-An Li, Ling-Hui Mou, Kurt Yun Roffler, Steve R. Wang, Shu-Ping Yeh, Chi-Tai Yao, Chi-Yuan Hou, Hsin-An Chou, Wen-Chien Tien, Hwei-Fang Yang, Ruey-Bing |
author_sort | Sahoo, Binay K. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10153537 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-101535372023-05-03 Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia Sahoo, Binay K. Lin, Yuh-Charn Tu, Cheng-Fen Lin, Chien-Chin Liao, Wei-Ju Li, Fu-An Li, Ling-Hui Mou, Kurt Yun Roffler, Steve R. Wang, Shu-Ping Yeh, Chi-Tai Yao, Chi-Yuan Hou, Hsin-An Chou, Wen-Chien Tien, Hwei-Fang Yang, Ruey-Bing Haematologica ARTICLE - Acute Myeloid Leukemia 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. Fondazione Ferrata Storti 2022-08-25 /pmc/articles/PMC10153537/ /pubmed/36005562 http://dx.doi.org/10.3324/haematol.2022.281151 Text en Copyright© 2023 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | ARTICLE - Acute Myeloid Leukemia Sahoo, Binay K. Lin, Yuh-Charn Tu, Cheng-Fen Lin, Chien-Chin Liao, Wei-Ju Li, Fu-An Li, Ling-Hui Mou, Kurt Yun Roffler, Steve R. Wang, Shu-Ping Yeh, Chi-Tai Yao, Chi-Yuan Hou, Hsin-An Chou, Wen-Chien Tien, Hwei-Fang Yang, Ruey-Bing Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia |
title | Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia |
title_full | Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia |
title_fullStr | Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia |
title_full_unstemmed | Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia |
title_short | Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemia |
title_sort | signal peptide-cub-egf-like repeat-containing protein 1-promoted flt3 signaling is critical for the initiation and maintenance of mll-rearranged acute leukemia |
topic | ARTICLE - Acute Myeloid Leukemia |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153537/ https://www.ncbi.nlm.nih.gov/pubmed/36005562 http://dx.doi.org/10.3324/haematol.2022.281151 |
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