title: Genomic instability is a principle pathologic feature of FLT3 ITD kinase activity in acute myeloid leukemia leading to clonal evolution and disease progression.
abstract: Acute Myeloid Leukemia with FLT3 ITD mutations are associated with a poor prognosis characterized by a higher relapse rate, shorter relapse free survival, and decreased likelihood of response to therapy at relapse. FLT3 ITD signaling drives cell proliferation and survival. FLT3 ITD AML disease progression is associated with cytogenetic evolution and acquired tyrosine kinase inhibitor (TKI) resistance suggesting a potential role of genomic instability. There is growing evidence demonstrating a relationship between FLT3 signaling and increased DNA damage, specifically through increased reactive oxygen species (ROS) resulting in double-strand breaks (DSB), as well as impaired DNA repair, involving deficiencies in the non-homologous end joining (NHEJ), alternative non-homologous end joining (ALT NHEJ) and homologous recombination (HR) pathways. The role of genomic instability in the pathogenesis of FLT3 ITD AML warrants further examination as it offers potential therapeutic targets.
authors.affiliation: a Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore , MD , USA.
authors.forename: Melanie T
authors.initials: MT
authors.lastname: Rebechi
authors.affiliation: a Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore , MD , USA.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Pratz
mesh_terms: D000818:Animals; D060965:Clonal Evolution / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D004261:DNA Replication; D004195:Disease Models, Animal; D018450:Disease Progression; D020440:Gene Duplication; D042822:Genomic Instability; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009154:Mutation; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D051941:fms-Like Tyrosine Kinase 3
keywords: AML; DNA repair; FLT3; genomic instability