Open AccessUncovering the Genomic Landscape in Newly Diagnosed and Relapsed Pediatric Cytogenetically Normal FLT 3‐ ITD AML
Author(s) -
Buelow Daelynn R.,
Pounds Stanley B.,
Wang YongDong,
Shi Lei,
Li Yongjin,
Finkelstein David,
Shurtleff Sheila,
Neale Geoffrey,
Inaba Hiroto,
Ribeiro Raul C.,
Palumbo Reid,
Garrison Dominique,
Orwick Shelley J.,
Blachly James S.,
Kroll Karl,
Byrd John C.,
Gruber Tanja A.,
Rubnitz Jeffrey E.,
Baker Sharyn D.
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12669
Subject(s) - npm1 , fusion gene , biology , fusion transcript , mutation , myeloid leukemia , fms like tyrosine kinase 3 , cancer research , gene , genetics , oncology , medicine , karyotype , chromosome
Fms‐like tyrosine kinase 3 ( FLT 3 ) internal tandem duplication ( ITD ) mutations, common in pediatric acute myeloid leukemia ( AML ), associate with early relapse and poor prognosis. Past studies have suggested additional cooperative mutations are required for leukemogenesis in FLT 3 ‐ ITD + AML . Using RNA sequencing and a next‐generation targeted gene panel, we broadly characterize the co‐occurring genomic alterations in pediatric cytogenetically normal ( CN ) FLT 3 ‐ ITD + AML to gain a deeper understanding of the clonal patterns and heterogeneity at diagnosis and relapse. We show that chimeric transcripts were present in 21 of 34 (62%) of de novo samples, 2 (6%) of these samples included a rare reoccurring fusion partner BCL 11B . At diagnosis, the median number of mutations other than FLT 3 per patient was 1 (range 0–3), which involved 8 gene pathways; WT 1 and NPM 1 mutations were frequently observed (35% and 24%, respectively). Fusion transcripts and high variant allele frequency ( VAF ) mutants, which included WT 1 , NPM 1 , SMARCA 2 , RAD 21 , and TYK 2 , were retained from diagnosis to relapse. We did observe reduction in VAF of simple or single mutation clones, but VAF s were preserved or expanded in more complex clones with multiple mutations. Our data provide the first insight into the genomic complexity of pediatric CN FLT 3 ‐ ITD + AML and could help stratify future targeted treatment strategies.