title: Evaluating frequency of PML-RARA mutations and conferring resistance to arsenic trioxide-based therapy in relapsed acute promyelocytic leukemia patients.
abstract: The aim of the study is to better understand the mechanism of relapse and acquired clinical resistance to arsenic trioxide (ATO) and/or all-trans retinoic acid (ATRA). Thirty relapsed acute promyelocytic leukemia (APL) patients were followed. Fifteen patients experienced two or more relapses; nine patients had clinical resistance to ATO-based therapy. The frequency and clinical significance of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) mutational status using Sanger sequencing were evaluated. Overall, eight different types of mutations in the RARA region (V218D, R272Q, T278A, T291I, N299D, R294W, A300G, and L220_F228delinsP) were identified in 11 patients. Eight missense mutations (L211P, C213R, S214L, A216V, L217F, D219H, S221G, and D241G) were found in the PML portion of PML-RARA in 14 patients, with A216V as the predominant mutation. Eight patients were found to harbor both PML and RARA mutations over the course of the disease. The PML-region mutations were associated with response to ATO-based therapy (P < 0.0001), number of relapses (P = 0.001), and early relapse (P = 0.013). Notably, one case sampled at nine different time points showed alternating clonal dominance over the course of treatment. This study demonstrated frequent mutations of PML-RARA and supported a clonal selection model in relation to APL relapse and ATO resistance.
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Yinjun
authors: Y
authors: Lou
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Yafang
authors: Y
authors: Ma
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Jianai
authors: J
authors: Sun
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Xiujin
authors: X
authors: Ye
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Hanzhang
authors: H
authors: Pan
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Yungui
authors: Y
authors: Wang
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Wenbin
authors: W
authors: Qian
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Haitao
authors: H
authors: Meng
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Wenyuan
authors: W
authors: Mai
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: JingSong
authors: J
authors: He
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003.
authors: Hongyan
authors: H
authors: Tong
authors: Department of Hematology, Institute of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, 79# Qingchun Road, Hangzhou, China, 310003. zjuhematology@163.com.|Key Laboratory of Hematopoietic Malignancies, Hangzhou, Zhejiang Province, China. zjuhematology@163.com.
authors: Jie
authors: J
authors: Jin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010087:Oxides / Q000008:administration & dosage*; D012008:Recurrence; D055815:Young Adult
chemical_list: D001152:Arsenicals; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D000077237:Arsenic Trioxide
keywords: Acute promyelocytic leukemia; Arsenic trioxide; PML-RARA mutation; Relapse; Resistance