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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >The potential role of Nutlins in the treatment of B-chronic lymphocytic leukemia (B-CLL)
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The potential role of Nutlins in the treatment of B-chronic lymphocytic leukemia (B-CLL)

机译：Nutlins在治疗B型慢性淋巴细胞性白血病（B-CLL）中的潜在作用

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In their recent study, Secchiero and collegues demonstrated that p53 is the major determinant of responsiveness to mouse double minute 2 inhibitors, such as Nutlin-3a. Of note, four different studies [2-5] suggest that p53 immunoblotting on B-chronic lymphocytic leukemia (B-CLL) cells pre- and post-treatment with Nudins should enter into the clinical practice to monitor the p53 status, as an aberrant p53 response to Nutlins (absence of p53 induction of unmodified, high basal levels of p53 protein) was associated to an aggressive disease course. Saddler et al. added the important information that p53 immunoblotting pre- and post-treatment with Nutlins is more informative on p53 defects, with respect to fluorescence in situ hybridization, to detect TP53 loss and p53 exon resequencing. Another important finding emerging from all of these studies [1-5] was the demonstration that untreated patients that displayed high sensitivity to treatment ex vivo with Nutlins progressed significantly more rapidly and required therapy earlier than patients with relatively less-sensitive CLL cells. Although it is recognized that a considerable heterogeneity characterizes the in vitro survival of B-CLL samples, it is noteworthy that a previous study has demonstrated that the spontaneous apoptosis of B-CLL cells in vitro is significantly higher in samples with poor prognosis cytogenetics . In line with these data challenging the traditional view that B-CLL disease derives from an inherent defect in apoptosis, it has been demonstrated that between 1 X 10~9 and 1 X 10~(12) cells (0.1-1.75% of the whole B-CLL clone) are born each day in vivo in all B-CLL patients studied . Thus, a dynamic interplay between birth (cell proliferation) and death characterizes B-CLL with higher birth rates (birth >0.35% of the clone per day) associated to disease progression . Moreover, the group of Efremov has demonstrated recendy that B-CLL with a poor prognosis displays increased proliferation also in vitro in response to TLR9 engagement by synthetic CpG oligodeoxynucleotides. This assay-the same used by Secchiero et al. in their study recently published in Journal of Leukocyte Biology-offers the possibility to analyze multiple parameters, such as proliferation, apoptosis, and markers of immune activation [1, 6]. Thus, Nutlins are potentially efficacious, not only in inducing B-CLL apoptosis [1-5] but also in restraining proliferation of p53 B-CLL cells obtained from patients with a relevant, negative prognostic marker, such as Zap-70~(high) levels . In light of the high proliferative activity of aggressive B-CLL , in a therapeutic perspective, the cytostatic activity of Nutlins might be as important as their proapoptotic activity. Considering the poor prognosis of B-CLL patients with high-risk disease, despite improvements in response rates using chemoimmunotherapycombinations [10], we believe that use of Nutlins alone or in combination with currently available therapeutic regimens will represent one important approach to ameliorate the therapeutic outcome in the vast majority of patients with wildtypep53 B-CLL.
机译：在他们的最新研究中，Secchiero和同事证实了p53是对小鼠double minutes 2抑制剂（例如Nutlin-3a）反应性的主要决定因素。值得注意的是，四项不同的研究[2-5]表明，用Nudins治疗前后的B慢性淋巴细胞性白血病（B-CLL）细胞的p53免疫印迹应进入临床实践，以监测p53的状态，这是异常的。对Nutlins的p53应答（不存在未修饰的，高基础水平的p53蛋白的p53诱导）与侵略性疾病进程相关。 Saddler等。补充了重要的信息，即用Nutlins进行的p53免疫印迹治疗前后，在荧光原位杂交方面可以更有效地检测p53缺陷，以检测TP53缺失和p53外显子重测序。从所有这些研究中得出的另一个重要发现[1-5]是证明，对具有Nutlins的离体治疗表现出高敏感性的未经治疗的患者比具有相对较低的CLL细胞的患者进展更快，需要更早的治疗。尽管已经认识到B-CLL样品的体外存活具有相当大的异质性，但值得注意的是，先前的研究表明，在预后较差的细胞遗传学样品中B-CLL细胞的体外自发凋亡明显更高。与这些挑战传统观点的数据一致，即B-CLL疾病是由细胞凋亡的固有缺陷引起的，已证明在1 X 10〜9到1 X 10〜（12）细胞之间（占整个细胞的0.1-1.75％）在所有研究的B-CLL患者中，B-CLL克隆每天都在体内出生。因此，出生（细胞增殖）与死亡之间的动态相互作用以B-CLL为特征，其具有与疾病进展相关的较高出生率（每天出生克隆的> 0.35％）。此外，Efremov研究组证明，预后较差的B-CLL在体外也响应合成CpG寡脱氧核苷酸对TLR9的参与而显示出增加的增殖。该测定法与Secchiero等人使用的相同。他们最近发表在《白细胞生物学杂志》上的研究中提供了分析多种参数的可能性，例如增殖，凋亡和免疫激活标记[1，6]。因此，nutlins具有潜在的功效，不仅可以诱导B-CLL凋亡[1-5]，而且可以抑制从具有相关不良预后标记物（例如Zap-70〜）的患者获得的p53 B-CLL细胞的增殖。 ）水平。鉴于侵略性B-CLL的高增殖活性，从治疗的角度来看，Nutlins的细胞抑制活性可能与其促凋亡活性一样重要。考虑到B-CLL合并高危疾病的患者预后较差，尽管使用化学免疫疗法联合治疗可提高反应率[10]，我们认为单独使用Nutlins或与目前可用的治疗方案结合使用将代表改善治疗的一种重要方法绝大多数野生型p53 B-CLL患者的预后。

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