T-cell acute lymphoblastic leukemias express a unique truncated FAT1 isoform that cooperates with NOTCH1 in leukemia development
Year: 2018
Type: article
Abstract: The human FAT1 gene was cloned over 20 years ago 1 , but there has only been an incremental understanding on its functional role in cancer and developmental disorders 2 .FAT1 is highly expressed in a large proportion of T-cell acute lymphoblastic leukemia (T-ALL) and B-cell ALL cases compared to their normal counterpart suggesting an oncogenic function 3 .Conversely, the FAT1 gene is also recurrently mutated in a small subset of T-ALL cases 4,5 and also in chronic lymphocytic leukemia 6 .Functionally, the FAT1 cadherin has been implicated in Wnt signaling 7 , hippo signaling 8 and more recently mitochondrial function 9 that together suggest a role outside the classical cadherin function in regulating cell-cell adhesion.Here we show that T-ALL cell lines and clinical samples express a unique N-terminal truncated FAT1 mRNA transcript that generates a protein from a novel transcriptional start site within a retained intronic sequence.This novel transcript is regulated independently from full length FAT1 and results in the expression of a truncated protein lacking almost the entire extracellular domain of FAT1.Significantly, this truncated protein is a novel bio-marker for T-ALL and found to cooperate with NOTCH in driving T-ALL in vivo, suggesting that in the context of T-ALL, this truncated protein may act as an oncogene.
Source: Haematologica
Institutions: VIB-KU Leuven Center for Cancer Biology, KU Leuven, QIMR Berghofer Medical Research Institute, UNSW Sydney, VIB-KU Leuven Center for Brain & Disease Research, University of Newcastle Australia, Inserm, Génomes, biologie cellulaire et thérapeutiques, Université Paris Diderot, Ghent University, Ghent University Hospital, Cancer Research Institute Ghent, Henan University, Henan Provincial People's Hospital
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,157
Funders: Cancer Research Institute, European Hematology Association, QIMR Berghofer Medical Research Institute, Institut National de la Santé et de la Recherche Médicale, University of New South Wales, Universitair Ziekenhuis Gent, KU Leuven, Universiteit Gent, Henan University, Assistance publique-Hôpitaux de Paris, Henan Provincial People's Hospital, Faculty of Medicine and Health, University of Sydney
Award: G1311324608
OpenAlex ID: W2902627440