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医学前沿

白血病不只是“一种病”

作者:http://www.handsomecare.com/ 发布时间:2016-06-29 浏览次数:1152

白血病不只是“一种病”

——翻译自纪念斯隆-凯特琳癌症中心官网

急性髓性白血病(AML),侵略性血癌,已被证明对于医生来说,评估和治疗都是非常棘手的。不同患者对治疗的反应有很大的不同,并且临床医师们发现几乎不可能预测谁将会恢复得很好,谁将会治疗无效。

一项新的研究分析了已知会导致疾病的超过100个基因揭示了这种差异的一个重要原因:AML不是一种基因混乱,而是造成特定的遗传变化至少11不同亚型。这一发现可能会改变患者诊断和治疗的方式。

分子遗传学家Elli Papaemmanuil说:“这些发现有助于我们了解基因突变是怎么样促使AML发生的——什么是白血病发生微小变化的关键。”他共同领导了这项研究,该研究今天在NEJM上发布了。“这是帮助我们可以确定谁需要积极的治疗,并选择谁可能从临床试验中受益的第一步。”

科学家们在《NEJM》上发表的这项研究发现,AML至少是11种不同的疾病,而且遗传改变可以帮助解释年轻AML患者存活状况的差异,为AML患者的临床试验及患者的诊断和治疗提供策略。

这是一项大规模研究,招募了1540AML患者,研究人员们分析了患者体内引发白血病的111个基因,其中86%的患者有2个以上驱动基因。这些被研究的患者可以被分为至少11个主要的研究组,每个都有不同的一组遗传改变和独特的临床特征。然而尽管研究者发现了常见的遗传机制,大部分患者在驱动白血病发生上均具有特殊的遗传改变组合,这种遗传复杂性或可帮助解释为何AML在患者的生存率上表现出了一定的差异性。

“这是第一次,我们解开AML基因组的遗传复杂性转换成不同的遗传亚群,反映了不同路径导致不同白血病的特定亚型,”Papaemmanuil博士解释说。 “这使我们能够理解的AML类型并使用该信息来开发临床方法,例如基于所述基因突变模式的临床试验疗法”。

AML的特征在于白血细胞的异常快速生长。它发展于骨髓前体细胞发生癌变,这是一系列DNA错误的结果。这通常要求控制血细胞产生的几个关键基因的错误。这种疾病会影响所有年龄的人,往往需要集中住院化疗几个月。

急性髓性白血病(AML)

虽然近年来研究人员已经鉴定了少数AML突变,在推动该疾病研究方面是有显著作用的。但多数患者具有许多额外的突变,可能是重要的,也可能不是重要的。这项新的研究阐明了许多这些突变之间的相互作用是如何影响疾病的进展。

纪念斯隆-凯特琳癌症中心MSK)的白血病研究员罗斯·莱文,在一篇对《新英格兰医学杂志》的社评中,引用罗伯特·弗罗斯特的诗歌“未选择的路”来描述不同的路径(基因突变)是如何导致不同的目的地(白血病)的。他写道,“这项研究提供了前所未有的清晰的对于不同的基因突变是如何导致不同白血病的解释,以及正常的血细胞是如何发展成白血病的具体路径,具有重要的生物学和临床意义。”

在这项研究中,对于患者的基因构成的完整认知大大提高了临床医生预测是否该患者会被目前的治疗方法治愈。

因为这项研究是如此之大,它让研究人员梳理出了以前没有认识到的基因的相互作用。例如,该分析显示不只是正在发生突变的组合,还有一个突变如何导致随后的突变。

 “一旦你扩展到大型基因队列,你就可以确定关系,而不仅仅是其中的突变简单组合,而是包括他们组合的顺序。”Papaemmanuil博士说:“这项研究为我们提供了白血病是如何发展的蓝图,这表明,这个蓝图到底是什么样的取决于病人的基因。”

这项研究说明提升癌症治愈率需要分析病人的基因资料。

2014年在纪念斯隆-凯特琳癌症中心(MSK)成立了The Marie-Josée and Henry R. Kravis Center中心,专门研究肿瘤分子生物学。采用了这项研究同样的方法,将临床资料和病人的肿瘤中分子信息的联系结合,再参照病人的预后和治疗后反映后反应。

更具体地说,MSK新成立的恶性血液病中心旨在利用这种类型的分子数据,以便更好地了解白血病是如何发展,然后将这些结果用于制定更好的治疗方法。

 

“这给了我们一个框架,回到实验室,在显微镜下真正地观察,明白这一切基因连接方式是如何发展成白血病的,”莱文博士说,“科学研究的基础就是去打开治好这个疾病的新思路和测试新的治疗方案。-【涵翔医疗翻译转载请注明出处】

原文:Acute myeloid leukemia (AML), an aggressive blood cancer, has proved to be tricky for doctors to assess and treat. Patients vary widely in their response to treatment, and clinicians have found it nearly impossible to predict who will do well and who will fare poorly.

 

A new study analyzing more than 100 genes known to cause the disease reveals a major reason for this disparity: AML is not one disorder but at least 11 distinct subtypes caused by specific genetic changes. This discovery could change the way patients are diagnosed and treated.

 

These findings help us understand how AML develops as mutations occur — what the critical events are that fine-tune the leukemia,” says Memorial Sloan Kettering molecular geneticist Elli Papaemmanuil, who co-led the study, which was published today in the New England Journal of Medicine (NEJM). “This is the first step in helping us to identify who needs aggressive treatments and to choose who might benefit from clinical trials.”

The study was conducted in collaboration with the Wellcome Trust Sanger Institute and a team of international colleagues. It involved analyzing leukemia-associated genes in 1,540 AML patients enrolled in three clinical trials in Europe — the largest AML patient group ever used for this type of genetic study. Researchers looked for common genetic themes behind development of the disease. They found that patients fit into at least 11 major groups, each with different assortments of genetic changes and distinctive clinical features.

 

For the first time, we untangled the genetic complexity of AML genomes into distinct genetic subgroups, reflecting paths leading to specific subtypes of AML,” Dr. Papaemmanuil explains. “This enables us to understand the biology of AML types and to use that information to develop clinical approaches such as combination therapies for clinical trials based on the mutation patterns.”

 

Mutational Profiles and AML Subtypes

AML is characterized by the rapid growth of abnormal white blood cells. It develops when precursor cells in the bone marrow become cancerous as a result of a series of errors in the DNA. This usually requires mistakes in several key genes controlling blood-cell production. The disease affects people of all ages and often requires months of intensive inpatient chemotherapy.

 

Although in recent years researchers have identified a handful of AML mutations that play a significant role in driving the disease, most patients have a number of additional mutations that may or may not be important. The new study clarifies how the interplay between many of these mutations can affect the disease’s progression.

MSK leukemia researcher Ross Levine, in an accompanying NEJM editorial, cited Robert Frost’s “The Road Not Taken” in describing how distinct paths — initiated by varying mutations — lead to different disease destinations. The study, he wrote, provides “an unprecedented understanding of the different roads that lead to AML and how the specific path from normal blood cell to leukemia has important biologic and clinical implications.”

 

In the study, full knowledge of the genetic makeup of a patient’s leukemia greatly improved clinicians’ ability to predict whether that patient would be cured with current treatments.

 

Because the study was so large, it allowed researchers to tease out genetic interactions that were not previously recognized. For example, the analysis showed patterns not just in the combination of mutations that occur but also in how one mutation can lead to a subsequent aberration.

 

Once you expand to a large cohort, you identify relationships, not just in the combination of which mutations come together but also in the order in which they’re acquired,” Dr. Papaemmanuil says.

 

This work provides us with a blueprint for how leukemia develops,” Dr. Levine adds. “It shows that how that blueprint is written really matters for the patient.”

Validating Genomic Analysis

The study illustrates the promise of improving cancer care through genomic analysis of patient-derived samples.

 

The Marie-Josée and Henry R. Kravis Center for Molecular Oncology, established at MSK in 2014, is taking this approach by correlating molecular information from tumors with clinical data, including patients’ outcomes and responses to therapy.

More specifically, MSK’s newly established Center for Hematologic Malignancies seeks to use this type of molecular data to better understand how leukemia develops — and then to apply those findings to crafting better therapies.

 

This gives us a framework to go back to the lab and understand how all this wiring contributes to leukemia — to really look under the hood,” Dr. Levine says. “This is the basis for scientific studies to unlock new ideas about this disease and to test new therapeutic ideas.”

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