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Background  The receptor tyrosine kinase  FLT3  with internal tandem duplications within the juxtamembrane domain ( FLT3 -ITD) is a poor prognostic factor; however, the prognostic significance of missense mutation in the tyrosine kinase domain ( FLT3 -TKD) is controversial. Furthermore, the accompanying mutations and fusion genes with  FLT3  mutations are unclear in acute myeloid leukemia (AML).    Methods  We investigated  FLT3  mutations and their correlation with other gene mutations and gene fusions through two RNA-seq based next-generation sequencing (NGS) method and prognostic impact in 207 de novo AML patients.    Results   FLT3 -ITD mutations were positive in 58 patients (28%), and  FLT3 -TKD mutations were positive in 20 patients (9.7%).  FLT  3-ITD  was associated with a higher white blood cell count (WBC, mean 72.9 × 10 9 /L vs. 24.2 × 10 9 /L,  P  = 0.000), higher bone marrow blasts (mean 65.9% vs. 56.0%,  P  = 0.024), and NK-AML (normal karyotype) (64.8% vs. 48.4%,  P  = 0.043).  NPM1  and  DNMT3A  mutations were enriched in  FLT3 -ITD (53.5% vs. 15.3%,  P  = 0.000; 34.6% vs. 13%,  P  = 0.003). However, the mutations of  CEBPA  were excluded in  FLT3 -AML (3.8% vs. 0% vs. 19.8%,  P  = 0.005). Mutations of  Ras  and  TP53  were unlikely associated with  FLT3 -ITD (1.9% vs. 20.6%,  P  = 0.006; 0% vs. 6.1%,  P  = 0.04). The common fusion genes (> 10%) in  FLT3 -ITD had  MLL- rearrangement and  NUP98 -rearrangement, while the common fusion genes in  FLT3 -TKD had  AML1-ETO  and  MLL -rearrangement. Two novel fusion genes  PRDM16-SKI  and  EFAN2-ZNF238  were identified in FLT3-ITD patients. Gene fusions and  NPM1  mutation were mutually excluded in  FLT3 -ITD and  FLT3 -TKD patients. Their patterns of mutual exclusivity and cooperation among mutated genes suggest that additional driver genetic alterations are required and reveal two evolutionary patterns of  FLT3  pathogenesis. Patients with  FLT3 -ITD had a lower CR (complete remission) rate, lower 3-year OS (overall survival), DFS (disease-free survival), and EFS (event-free survival) compared to  FLT3  wt AML. NK-AML with  FLT3 -ITD had a lower 3-year OS, DFS, and EFS than those without, while  FLT3 -TKD did not influence the survival in whole cohort and NK-AML. Besides, we found that  FLT3 -ITD/ TET2  bimutation defined a poor prognostic subgroup.    Conclusions  Our study offers deep insights into the molecular pathogenesis and biology of AML with  FLT3 -ITD and  FLT3 -TKD by providing the profiles of concurrent molecular alterations and the clinical impact of  FLT3 -ITD and  FLT3 -TKD on AML patients.

experimental hematology and oncology

Profiling of somatic mutations and fusion genes in acute myeloid leukemia patients with FLT3-ITD or FLT3-TKD mutation at diagnosis reveals distinct evolutionary patterns