Genomic instability is a principle pathologic feature of FLT3 ITD kinase activity in acute myeloid leukemia leading to clonal evolution and disease progression

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 progr...

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Bibliographic Details
Published in:Leukemia & lymphoma 2017-09, Vol.58 (9), p.2040-2050
Main Authors: Rebechi, Melanie T., Pratz, Keith W.
Format: Article
Language:English
Subjects:
AML
Animals
Clonal Evolution - genetics
Disease Models, Animal
Disease Progression
DNA Damage - drug effects
DNA repair
DNA Repair - drug effects
DNA Replication
FLT3
fms-Like Tyrosine Kinase 3 - genetics
Gene Duplication
Genomic Instability
Humans
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - pathology
Mice
Mutation
Tandem Repeat Sequences
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Summary: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.
ISSN:1042-8194
1029-2403
DOI:10.1080/10428194.2017.1283031