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Acute Myeloid Leukemia
Clinical significance of RAS pathway alter- ations in pediatric acute myeloid leukemia
Taeko Kaburagi,1,2 Genki Yamato,1,2 Norio Shiba,3 Kenichi Yoshida,4 Yusuke Hara,2 Ken Tabuchi,5 Yuichi Shiraishi,6 Kentaro Ohki,7 Manabu Sotomatsu,1 Hirokazu Arakawa,2 Hidemasa Matsuo,8 Akira Shimada,9 Tomohiko Taki,10 Nobutaka Kiyokawa,7 Daisuke Tomizawa,11 Keizo Horibe,12 Satoru Miyano,13 Takashi Taga,14 Souichi Adachi,8 Seishi Ogawa4 and Yasuhide Hayashi1,15
1Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma; 2Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma; 3Department of Pediatrics, Yokohama City University Hospital, Kanagawa; 4Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto; 5Department of Pediatrics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo; 6Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo; 7Department of Pediatric Hematology and Oncology Research, National Research institute for Child Health and Development, Tokyo; 8Human Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto; 9Department of Pediatrics, Okayama University, Okayama; 10Department or Medical Technology, Kyorin University Faculty of Health Sciences, Tokyo; 11Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, Tokyo; 12Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi; 13Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, Tokyo University, Tokyo; 14Department of Pediatrics, Shiga University of Medical Science, Shiga and 15Institute of Physiology and Medicine, Jobu University, Gunma, Japan.
ABSTRACT
RAS pathway alterations have been implicated in the pathogenesis of various hematological malignancies. However, their clinical rel- evance in pediatric acute myeloid leukemia (AML) is not well char- acterized. We analyzed the frequency, clinical significance, and prognos- tic relevance of RAS pathway alterations in 328 pediatric patients with de novo AML. RAS pathway alterations were detected in 80 (24.4%) of 328 patients: NF1 (n=7, 2.1%), PTPN11 (n=15, 4.6%), CBL (n=6, 1.8%), NRAS (n=44, 13.4%), KRAS (n=12, 3.7%). Most of these alterations in the RAS pathway were mutually exclusive also together with other aber- rations of signal transduction pathways such as FLT3-ITD (P=0.001) and KIT mutation (P=0.004). NF1 alterations were frequently detected in patients with complex karyotype (P=0.031) and were found to be inde- pendent predictors of poor overall survival (OS) in multivariate analysis (P=0.007). At least four of seven patients with NF1 alterations had bi- allelic inactivation. NRAS mutations were frequently observed in patients with CBFB-MYH11 and were independent predictors of favor- able outcomes in multivariate analysis (OS, P=0.023; event-free survival [EFS], P=0.037). Patients with PTPN11 mutations more frequently received stem cell transplantation (P=0.035) and showed poor EFS than patients without PTPN11 mutations (P=0.013). Detailed analysis of RAS pathway alterations may enable a more accurate prognostic stratification of pediatric AML and may provide novel therapeutic molecular targets related to this signal transduction pathway.
Introduction
Acute myeloid leukemia (AML) is characterized by considerable genetic hetero- geneity. Several chromosomal aberrations and gene alterations have been identified in these patients; some of these have been found useful for risk stratification.1 Aberrations of signal transduction pathways (such as RAS family members, KIT, and FLT3) are considered as one of the most important pathogenetic factors in AML.2
Ferrata Storti Foundation
Haematologica 2022 Volume 107(3):583-592
Correspondence:
YASUHIDE HAYASHI
hayashiy@jobu.ac.jp hayashiy-tky@umin.ac.jp
Received: August 28, 2020. Accepted: March 12, 2021. Pre-published: March 18, 2021.
https://doi.org/10.3324/haematol.2020.269431 ©2022 Ferrata Storti Foundation
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