Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy
Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy
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DOI：
10.1182/blood-2017-02-763086
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发表时间：
2017-08-10
期刊：
影响因子：
20.3
通讯作者：
Rotter, Varda
中科院分区：
文献类型：
--
作者：
Prokocimer, Miron;Molchadsky, Alina;Rotter, Varda
急性髓细胞白血病（AML）的异质性和预后差，需要治疗的改进。目前AML研究的进展产生了关于AML遗传、表观遗传、进化和临床多样性的重要见解，所有这些都是功能失调的p53发挥关键作用。由于p53是造血干细胞功能的核心，其畸变影响AML演变、生物学和治疗反应，并且通常预测不良预后。虽然在人类实体瘤中，超过一半的病例中TP53发生突变，但TP53突变发生在不到十分之一的新发AML病例中。然而，野生型（wt）p53功能障碍，由于非突变p53异常似乎是相当频繁的各种AML实体，轴承，据推测，更大的影响比目前认识到的。因此，我们主张评估成人AML与共存的p53改变。因此，我们不仅关注突变型p53致癌性功能获得的影响，而且关注非突变型wtp53失活的潜在机制，这可能具有治疗意义。患者特异性TP53基因分型与p53蛋白的功能评价可能显着有助于精确评估AML中的p53状态，从而导致定制合理和精确的基于p53的治疗。p53功能障碍的潜在机制的解决将更好地解决目前考虑用于AML的p53靶向治疗。此外，提出了一种基于p53的AML诊断后处理的建议新算法，旨在促进基于p53的治疗选择。
The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices.