학술논문
Characterisation of FLT3 alterations in childhood acute lymphoblastic leukaemia.
Document Type
Academic Journal
Author
Gutierrez-Camino A; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Richer C; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Ouimet M; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Fuchs C; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Langlois S; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Khater F; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Caron M; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Beaulieu P; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; St-Onge P; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Bataille AR; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.; Sinnett D; Division of Hematology-Oncology, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada. daniel.sinnett@umontreal.ca.; Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada. daniel.sinnett@umontreal.ca.
Source
Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Alterations of FLT3 are among the most common driver events in acute leukaemia with important clinical implications, since it allows patient classification into prognostic groups and the possibility of personalising therapy thanks to the availability of FLT3 inhibitors. Most of the knowledge on FLT3 implications comes from the study of acute myeloid leukaemia and so far, few studies have been performed in other leukaemias.
Methods: A comprehensive genomic (DNA-seq in 267 patients) and transcriptomic (RNA-seq in 160 patients) analysis of FLT3 in 342 childhood acute lymphoblastic leukaemia (ALL) patients was performed. Mutations were functionally characterised by in vitro experiments.
Results: Point mutations (PM) and internal tandem duplications (ITD) were detected in 4.3% and 2.7% of the patients, respectively. A new activating mutation of the TKD, G846D, conferred oncogenic properties and sorafenib resistance. Moreover, a novel alteration involving the circularisation of read-through transcripts (rt-circRNAs) was observed in 10% of the cases. Patients presenting FLT3 alterations exhibited higher levels of the receptor. In addition, patients with ZNF384- and MLL/KMT2A-rearranged ALL, as well as hyperdiploid subtype, overexpressed FLT3.
Discussion: Our results suggest that specific ALL subgroups may also benefit from a deeper understanding of the biology of FLT3 alterations and their clinical implications.
(© 2023. The Author(s).)
Methods: A comprehensive genomic (DNA-seq in 267 patients) and transcriptomic (RNA-seq in 160 patients) analysis of FLT3 in 342 childhood acute lymphoblastic leukaemia (ALL) patients was performed. Mutations were functionally characterised by in vitro experiments.
Results: Point mutations (PM) and internal tandem duplications (ITD) were detected in 4.3% and 2.7% of the patients, respectively. A new activating mutation of the TKD, G846D, conferred oncogenic properties and sorafenib resistance. Moreover, a novel alteration involving the circularisation of read-through transcripts (rt-circRNAs) was observed in 10% of the cases. Patients presenting FLT3 alterations exhibited higher levels of the receptor. In addition, patients with ZNF384- and MLL/KMT2A-rearranged ALL, as well as hyperdiploid subtype, overexpressed FLT3.
Discussion: Our results suggest that specific ALL subgroups may also benefit from a deeper understanding of the biology of FLT3 alterations and their clinical implications.
(© 2023. The Author(s).)