科學家揭示骨髓惡性腫瘤克隆進化的歷程
作者：
小柯機器人發布時間：2020/10/31 20:30:45
美國斯隆·凱特琳紀念癌症中心Ross L. Levine小組近日取得一項新成果。經過不懈努力，他們利用單細胞突變分析了骨髓惡性腫瘤克隆的進化。相關論文於2020年10月28日在線發表於《自然》雜誌。
為了揭示骨髓惡性腫瘤的克隆結構，探究人員對來自123位患者的146個樣本進行了單細胞突變分析。
研究發現急性骨髓性白血病（AML）是由少數克隆控制，這些克隆經常在表觀遺傳調控因子中同時發生突變。相反，信號基因的突變通常頻繁發生在不同的亞克隆中，這與克隆多樣性的增加是一致的。研究人員描繪了每個樣本的克隆軌跡，並發現了協同促進克隆擴增的突變組合。最後，研究人員將蛋白質表達與突變分析相結合揭示了體細胞基因型和具有免疫表型的克隆結構。該發現為了解髓樣轉化的發病機理以及克隆複雜性如何隨疾病的進展而發展提供了基礎。
據悉，包括AML在內的骨髓惡性腫瘤是由造血幹細胞和獲得體細胞突變的祖細胞擴增造成的。大量分子生物學分析表明突變是逐步獲得的：具有高等位基因頻率的突變出現在白細胞生成早期，而具有低等位基因頻率的突變則被認為是隨後出現的。儘管批量測序可以提供有關白血病生物學和預後的信息，但是它無法區分同一克隆中發生了哪些突變也無法準確測量克隆的複雜性或確定突變的順序。
附：英文原文
Title: Single-cell mutation analysis of clonal evolution in myeloid malignancies
Author: Linde A. Miles, Robert L. Bowman, Tiffany R. Merlinsky, Isabelle S. Csete, Aik T. Ooi, Robert Durruthy-Durruthy, Michael Bowman, Christopher Famulare, Minal A. Patel, Pedro Mendez, Chrysanthi Ainali, Benjamin Demaree, Cyrille L. Delley, Adam R. Abate, Manimozhi Manivannan, Sombeet Sahu, Aaron D. Goldberg, Kelly L. Bolton, Ahmet Zehir, Raajit Rampal, Martin P. Carroll, Sara E. Meyer, Aaron D. Viny, Ross L. Levine
Issue&Volume: 2020-10-28
Abstract: Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later1–3. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.
DOI: 10.1038/s41586-020-2864-x
Source: https://www.nature.com/articles/s41586-020-2864-x