Gourdin Theodore S, Zou Ying, Ning Yi, Emadi Ashkan, Duong Vu H, Tidwell Michael L, Chen Ching, Rassool Feyruz V, Baer Maria R
University of Maryland Greenebaum Cancer Center, Baltimore, MD; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD.
Cancer Genet. 2014 Oct-Dec;207(10-12):467-73. doi: 10.1016/j.cancergen.2014.09.001. Epub 2014 Sep 16.
FLT3 internal tandem duplication (ITD) mutations are present in acute myeloid leukemia (AML) in 30% of patients with acute myeloid leukemia (AML), most commonly in those with a normal karyotype, and are associated with short relapse-free survival. Both in vitro and in vivo studies of FLT3-ITD cell lines have demonstrated reactive oxygen species-mediated DNA double-strand breaks and associated error-prone DNA repair as a mechanism of genomic instability, and we hypothesized that genomic instability might be manifested by cytogenetic changes at relapse of FLT3-ITD AML. We retrospectively reviewed charts of patients with cytogenetically normal (CN) FLT3-ITD AML treated at the University of Maryland Greenebaum Cancer Center, with attention to metaphase analysis results at relapse. Cytogenetic data were available from first and, when applicable, subsequent relapses for 15 patients diagnosed with CN FLT3-ITD AML. Among 12 patients with documented FLT3-ITD at first and, when applicable, subsequent relapse, 10 had cytogenetic changes, including nine with rare structural abnormalities. The high frequency of rare structural chromosome abnormalities at relapse in our case series supports a role of genomic instability in the genesis of relapse, and suggests that reactive oxygen species-generating and DNA repair pathways might be therapeutic targets in FLT3-ITD AML.
FLT3内部串联重复(ITD)突变存在于30%的急性髓系白血病(AML)患者中,最常见于核型正常的患者,且与无复发生存期短相关。对FLT3-ITD细胞系的体外和体内研究均表明,活性氧介导的DNA双链断裂以及相关的易出错DNA修复是基因组不稳定的一种机制,我们推测基因组不稳定可能在FLT3-ITD AML复发时通过细胞遗传学改变表现出来。我们回顾性分析了在马里兰大学格林ebaum癌症中心接受治疗的细胞遗传学正常(CN)FLT3-ITD AML患者的病历,重点关注复发时的中期分析结果。15例诊断为CN FLT3-ITD AML的患者有首次及(如适用)后续复发时的细胞遗传学数据。在12例首次及(如适用)后续复发时记录有FLT3-ITD的患者中,10例有细胞遗传学改变,其中9例有罕见的结构异常。我们病例系列中复发时罕见结构染色体异常的高频率支持了基因组不稳定在复发发生中的作用,并表明产生活性氧和DNA修复途径可能是FLT3-ITD AML的治疗靶点。