Evolution of acute myelogenous leukemia stem cell properties after treatment and progression
Evolution of acute myelogenous leukemia stem cell properties after treatment and progression
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DOI：
10.1182/blood-2016-02-695312
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发表时间：
2016-09-29
期刊：
影响因子：
20.3
通讯作者：
Becker, Michael W.
中科院分区：
文献类型：
--
作者：
Ho, Tzu-Chieh;LaMere, Mark;Becker, Michael W.
大多数癌症随着时间的推移而演变，因为患者最初对治疗有反应，在复发时对相同的药物产生抗药性。癌症干细胞被认为是治疗难耐药的复发储存库，但这一模式缺乏正式的证据。我们前瞻性地描述了确诊和复发的急性髓细胞白血病(AML)患者队列中的白血病干细胞群(LSCs)，以评估病程对这些关键人群的影响。采集初诊AML患者治疗前和复发后的白血病样本，用限制性稀释分析评估LSC频率。通过荧光标记细胞分选和移植到免疫缺陷NOD/SCID/IL-2受体γ链缺失小鼠体内，鉴定LSC群体。为已发表的LSC标志物确定治疗前和复发后LSC的表面抗原表达谱。我们证明，在确诊和复发之间，LSC的频率增加了9到90倍。在治疗和复发前没有表现出这种活性的白血病原始细胞群体中，发现复发时的LSC活性。此外，我们描述了伴随着这些新的LSC群体进化而来的遗传不稳定性和特殊的表型变化。这项研究首次表征了化疗后LSCs在体内的演变，发现当疾病进展时，原始AML细胞的生理学发生了戏剧性的变化。综上所述，这些发现提供了一个新的参考框架，用于评估应考虑疾病控制和更高级疾病诱导的AML候选疗法。
Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immuno-deficient NOD/SCID/interleukin 2 receptor gamma chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered.