Rebechi Melanie T, Pratz Keith W
a Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University , Baltimore , MD , USA.
Leuk Lymphoma. 2017 Sep;58(9):1-11. doi: 10.1080/10428194.2017.1283031. Epub 2017 Feb 6.
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.
伴有FLT3内部串联重复（ITD）突变的急性髓系白血病与预后不良相关，其特征为复发率较高、无复发生存期较短以及复发时对治疗产生反应的可能性降低。FLT3 ITD信号传导驱动细胞增殖和存活。FLT3 ITD急性髓系白血病疾病进展与细胞遗传学演变和获得性酪氨酸激酶抑制剂（TKI）耐药相关，提示基因组不稳定可能发挥作用。越来越多的证据表明FLT3信号传导与DNA损伤增加之间存在关联，特别是通过活性氧（ROS）增加导致双链断裂（DSB），以及DNA修复受损，包括非同源末端连接（NHEJ）、替代非同源末端连接（ALT NHEJ）和同源重组（HR）途径存在缺陷。基因组不稳定在FLT3 ITD急性髓系白血病发病机制中的作用值得进一步研究，因为它提供了潜在的治疗靶点。
