英国牛津大学Adam J. Mead和David C. Wedge研究组合作，对子宫内起源的成人同卵双胞胎骨髓纤维化病例进行分析。相关论文发表在2022年5月30日出版的《自然—医学》杂志上。

他们描述了一个显著的单卵双胞胎病例，其表现为 CALR 突变阳性骨髓增殖性肿瘤 (MPN)（年龄分别为 37 和 38 岁），临床表型为原发性骨髓纤维化。T 细胞和真皮成纤维细胞中不存在 CALR 突变，证实了体细胞获得。全基因组测序谱系追踪揭示了 CALR 突变 MPN 克隆的共同克隆起源，其发生在子宫内，然后是双胞胎经胎盘传播和随后的类似疾病潜伏期。指标分选和单菌落基因分型显示表型造血干细胞 (HSC) 可能是 MPN 增殖细胞。

此外，新生儿血斑分析证实了一名真性红细胞增多症患者（34 岁）的 JAK2V617F 突变在子宫内起源。这些发现为了解 MPN 的长期进化动力学和 HSC 中 MPN 相关驱动突变所发挥的适应性优势提供了一个独特的窗口。

据了解，单细胞获得起始体细胞驱动突变与癌症临床表现之间的潜伏期在很大程度上是未知的。

附：英文原文

Title: In utero origin of myelofibrosis presenting in adult monozygotic twins

Author: Sousos, Nikolaos, N Leathlobhair, Mire, Simoglou Karali, Christina, Louka, Eleni, Bienz, Nicola, Royston, Daniel, Clark, Sally-Ann, Hamblin, Angela, Howard, Kieran, Mathews, Vikram, George, Biju, Roy, Anindita, Psaila, Bethan, Wedge, David C., Mead, Adam J.

Issue&Volume: 2022-05-30

Abstract: The latency between acquisition of an initiating somatic driver mutation by a single-cell and clinical presentation with cancer is largely unknown. We describe a remarkable case of monozygotic twins presenting with CALR mutation-positive myeloproliferative neoplasms (MPNs) (aged 37 and 38 years), with a clinical phenotype of primary myelofibrosis. The CALR mutation was absent in T cells and dermal fibroblasts, confirming somatic acquisition. Whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Index sorting and single-colony genotyping revealed phenotypic hematopoietic stem cells (HSCs) as the likely MPN-propagating cell. Furthermore, neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation in a patient presenting with polycythemia vera (aged 34 years). These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs. Lineage tracing analyses of cells from two monozygotic twins presenting with myelofibrosis in adulthood provide evidence of in utero transplacental transmission of the tumorigenic clone.

DOI: 10.1038/s41591-022-01793-4

Source: https://www.nature.com/articles/s41591-022-01793-4